64 results on '"Alexander Pasternak"'
Search Results
2. Pharmacological inhibition of hematopoietic progenitor kinase 1 positively regulates T-cell function.
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Yun Wang, Kelvin Zhang, Peter Georgiev, Steven Wells, Haiyan Xu, Brian M Lacey, Zangwei Xu, Jason Laskey, Robbie Mcleod, Joey L Methot, Mark Bittinger, Alexander Pasternak, and Sheila Ranganath
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Medicine ,Science - Abstract
Hematopoietic progenitor kinase 1 (HPK1), a hematopoietic cell-specific Ste20-related serine/threonine kinase, is a negative regulator of signal transduction in immune cells, including T cells, B cells, and dendritic cells (DCs). In mice, HPK1 deficiency subverts inhibition of the anti-tumor immune response and is associated with functional augmentation of anti-tumor T cells. We have used a potent, small molecule HPK1 inhibitor, Compound 1, to investigate the effects of pharmacological intervention of HPK1 kinase activity in immune cells. Compound 1 enhanced Th1 cytokine production in T cells and fully reverted immune suppression imposed by the prostaglandin E2 (PGE2) and adenosine pathways in human T cells. Moreover, the combination of Compound 1 with pembrolizumab, a humanized monoclonal antibody against the programmed cell death protein 1 (PD-1), demonstrated a synergistic effect, resulting in enhanced interferon (IFN)-γ production. Collectively, our results suggest that blocking HPK1 kinase activity with small molecule inhibitors alone or in combination with checkpoint blockade may be an attractive approach for the immunotherapy of cancer.
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- 2020
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3. O8 Cell-associated HIV-1 unspliced RNA level predicts both time to virological suppression and duration of post-treatment virological control in patients treated with temporary early ART
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Alexander Pasternak, Jan Prins, and Ben Berkhout
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Microbiology ,QR1-502 ,Public aspects of medicine ,RA1-1270 - Published
- 2016
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4. Cell-associated HIV-1 multiply spliced RNA level is an independent predictor of disease progression without ART and CD4:CD8 ratio normalization on ART
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Alexander Pasternak, Jan Prins, and Ben Berkhout
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Microbiology ,QR1-502 ,Public aspects of medicine ,RA1-1270 - Published
- 2016
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5. Immune and viral correlates of 'secondary viral control' after treatment interruption in chronically HIV-1 infected patients.
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Ellen Van Gulck, Lotte Bracke, Leo Heyndrickx, Sandra Coppens, Derek Atkinson, Céline Merlin, Alexander Pasternak, Eric Florence, and Guido Vanham
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Medicine ,Science - Abstract
Upon interruption of antiretroviral therapy, HIV-infected patients usually show viral load rebound to pre-treatment levels. Four patients, hereafter referred to as secondary controllers (SC), were identified who initiated therapy during chronic infection and, after stopping treatment, could control virus replication at undetectable levels for more than six months. In the present study we set out to unravel possible viral and immune parameters or mechanisms of this phenomenon by comparing secondary controllers with elite controllers and non-controllers, including patients under HAART. As candidate correlates of protection, virus growth kinetics, levels of intracellular viral markers, several aspects of HIV-specific CD4+ and CD8+ T cell function and HIV neutralizing antibodies were investigated. As expected all intracellular viral markers were lower in aviremic as compared to viremic subjects, but in addition both elite and secondary controllers had lower levels of viral unspliced RNA in PBMC as compared to patients on HAART. Ex vivo cultivation of the virus from CD4+ T cells of SC consistently failed in one patient and showed delayed kinetics in the three others. Formal in vitro replication studies of these three viruses showed low to absent growth in two cases and a virus with normal fitness in the third case. T cell responses toward HIV peptides, evaluated in IFN-γ ELISPOT, revealed no significant differences in breadth, magnitude or avidity between SC and all other patient groups. Neither was there a difference in polyfunctionality of CD4+ or CD8+ T cells, as evaluated with intracellular cytokine staining. However, secondary and elite controllers showed higher proliferative responses to Gag and Pol peptides. SC also showed the highest level of autologous neutralizing antibodies. These data suggest that higher T cell proliferative responses and lower replication kinetics might be instrumental in secondary viral control in the absence of treatment.
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- 2012
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6. Rapid Evolution of a Fragment-like Molecule to Pan-Metallo-Beta-Lactamase Inhibitors: Initial Leads toward Clinical Candidates
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Mihirbaran Mandal, Li Xiao, Weidong Pan, Giovanna Scapin, Guoqing Li, Haiqun Tang, Shu-Wei Yang, Jianping Pan, Yuriko Root, Reynalda Keh de Jesus, Christine Yang, Winnie Prosise, Priya Dayananth, Asra Mirza, Alex G. Therien, Katherine Young, Amy Flattery, Charles Garlisi, Rumin Zhang, Donald Chu, Payal Sheth, Inhou Chu, Jin Wu, Carrie Markgraf, Hai-Young Kim, Ronald Painter, Todd W. Mayhood, Edward DiNunzio, Daniel F. Wyss, Alexei V. Buevich, Thierry Fischmann, Alexander Pasternak, Shuzhi Dong, Jacqueline D. Hicks, Artjohn Villafania, Lianzhu Liang, Nicholas Murgolo, Todd Black, William K. Hagmann, Jim Tata, Emma R. Parmee, Ann E. Weber, Jing Su, and Haifeng Tang
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Drug Discovery ,Molecular Medicine - Abstract
With the emergence and rapid spreading of NDM-1 and existence of clinically relevant VIM-1 and IMP-1, discovery of pan inhibitors targeting metallo-beta-lactamases (MBLs) became critical in our battle against bacterial infection. Concurrent with our fragment and high-throughput screenings, we performed a knowledge-based search of known metallo-beta-lactamase inhibitors (MBLIs) to identify starting points for early engagement of medicinal chemistry. A class of compounds exemplified by
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- 2022
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7. 1723. MK-3866, a metallo-β-lactamase inhibitor, is not subject to efflux in Pseudomonas aeruginosa
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Katherine Young, Asra Mirza, Carl Balibar, Shuzhi Dong, Frank Bennett, Jinlong Jiang, Haiqun Tang, Claire Tudge, Jack Scott, Dexi Yang, and Alexander Pasternak
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Infectious Diseases ,Oncology - Abstract
Background Metallo-beta (β)-lactamases (MBLs) are in the class B group of β-lactamases due to zinc ions in the active site that are required for enzymatic activity. MK-3866 is a small molecule MBL inhibitor (MBLi) that restores antibacterial activity against resistant MBL-expressing gram-negative bacteria. Efflux is an important mechanism of antibiotic resistance in Pseudomonas aeruginosa (Pa). Imipenem (IMI) is not subject to efflux and neither is relebactam (REL), a β-lactamase inhibitor (BLi) of class A and C β-lactamases that is approved in combination with IMI/cilastatin. An efflux assay was devised to characterize MBLis for potentiation of IMI or cefepime (FEP) in isogenic strain pairs of efflux wild-type and multiply efflux deleted (MED) strains of Pa. Our objective was to determine if MK-3866 and related analogs are subject to efflux in Pa. Methods Bacterial isolates were engineered to demonstrate the ability of MBLis to be effluxed by introducing IMI metallo-β-lactamase-1 (IMP-1) (by electroporation) or Verona integron-encoded metallo-β-lactamases (VIM-1, VIM-2) (utilizing the cloning vector pFlp2) into isogenic MED and wild-type (WT) Pa isolates. Susceptibility testing was performed with IMI or FEP at a fixed concentration equal to the Pa Clinical and Laboratory Standards Institute susceptibility breakpoint for each and including a fixed 4 µg/mL of REL to inhibit class A or C enzymes, referred to as the SLICE assay. The concentration of MK-3866 and analogues required to restore susceptibility to either antibiotic in WT and MED strains was assessed. Results MICs to the combination of MK-3866/REL/IMI or MK-3866/REL/FEP vary by ≤4-fold between the WT and MED strain of each isogenic strain pair (Table 1). In contrast, large differential MIC values (efflux ratios) can be seen for the MK-3866 analogues A and B, with more moderate efflux ratios observed for other analogues. The exact efflux ratio depended on the MBL studied and the antibiotic partner. Conclusion MK-3866 showed a low potential for efflux whether IMP-1, VIM-1, or VIM-2 was expressed, in contrast to analogues of MK-3866 which exhibited differentials from nominal to extreme (≥ 128-fold) between efflux WT versus MED isolates. Disclosures Katherine Young, M.S., Merck & Co., Inc.: Stocks/Bonds Asra Mirza, MS, Merck & Co., Inc.: Stocks/Bonds Carl Balibar, PhD, Merck & Co., Inc.: Stocks/Bonds Shuzhi Dong, PhD, Merck & Co., Inc.: Stocks/Bonds Frank Bennett, PhD, Merck & Co., Inc.: Stocks/Bonds Jinlong Jiang, PhD, Merck & Co., Inc.: Stocks/Bonds Haiqun Tang, PhD, Merck & Co., Inc.: Stocks/Bonds Claire Tudge, PhD, Merck & Co., Inc.: Stocks/Bonds Jack Scott, PhD, Merck & Co., Inc.: Stocks/Bonds Dexi Yang, PhD, Merck & Co., Inc.: Stocks/Bonds Alexander Pasternak, PhD, Merck & Co., Inc.: Stocks/Bonds.
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- 2022
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8. Discovery of Diaminopyrimidine Carboxamide HPK1 Inhibitors as Preclinical Immunotherapy Tool Compounds
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Joey L. Methot, David A Candito, Sheila Ranganath, Zangwei Xu, Xavier Fradera, Abdelghani Achab, Erin F. DiMauro, Haiyan Xu, Samuel M. Levi, Brandon A. Vara, Brian M. Lacey, Mark Bittinger, Jennifer Piesvaux, Dustin M Smith, Alexander Pasternak, Jongwon Lim, David Jonathan Bennett, J. Richard Miller, Charles A. Lesburg, and Shuhei Kawamura
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010405 organic chemistry ,Chemistry ,medicine.drug_class ,Kinase ,medicine.medical_treatment ,T cell ,Organic Chemistry ,T-cell receptor ,Carboxamide ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,Cytokine ,medicine.anatomical_structure ,Diaminopyrimidine ,Drug Discovery ,Cancer research ,medicine ,Kinome ,B cell - Abstract
[Image: see text] Hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase, is a negative immune regulator of T cell receptor (TCR) and B cell signaling that is primarily expressed in hematopoietic cells. Accordingly, it has been reported that HPK1 loss-of-function in HPK1 kinase-dead syngeneic mouse models shows enhanced T cell signaling and cytokine production as well as tumor growth inhibition in vivo, supporting its value as an immunotherapeutic target. Herein, we present the structurally enabled discovery of novel, potent, and selective diaminopyrimidine carboxamide HPK1 inhibitors. The key discovery of a carboxamide moiety was essential for enhanced enzyme inhibitory potency and kinome selectivity as well as sustained elevation of cellular IL-2 production across a titration range in human peripheral blood mononuclear cells. The elucidation of structure–activity relationships using various pendant amino ring systems allowed for the identification of several small molecule type-I inhibitors with promising in vitro profiles.
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- 2021
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9. Discovery of Potent and Orally Available Bicyclo[1.1.1]pentane-Derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors
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Nicolas Solban, Alexander Pasternak, Qinglin Pu, Amy C. Doty, David Jonathan Bennett, Charles A. Lesburg, Wensheng Yu, Prasanthi Geda, Nunzio Sciammetta, J. Richard Miller, Hua Zhou, Xuelei Song, Yongxin Han, Lars Neumann, David L. Sloman, Mangeng Cheng, Heidi Ferguson, Karin M. Otte, Liangqin Guo, Hongjun Zhang, Alfred Lammens, Xavier Fradera, and Meredeth A. McGowan
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Bicyclic molecule ,010405 organic chemistry ,Chemistry ,Stereochemistry ,Organic Chemistry ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Pentane ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,Amide ,Drug Discovery ,Moiety ,Potency ,Bioisostere ,Indoleamine 2,3-dioxygenase ,Benzamide - Abstract
[Image: see text] Indoleamine-2,3-dioxygenase 1 (IDO1) inhibition and its combination with immune checkpoint inhibitors like pembrolizumab have drawn considerable attention from both academia and the pharmaceutical industry. Here, we describe the discovery of a novel class of highly potent IDO1 heme-displacing inhibitors featuring a unique bicyclo[1.1.1]pentane motif. Compound 1, evolving from an ALIS (automated ligand identification system) hit, exhibited excellent potency but lacked the desired pharmacokinetic profile due to extensive amide hydrolysis of the benzamide moiety. Replacing the central phenyl ring in 1 with a bicyclo[1.1.1]pentane bioisostere effectively circumvented the amide hydrolysis issue, resulting in the discovery of compound 2 with a favorable overall profile such as excellent potency, selectivity, pharmacokinetics, and a low predicted human dose.
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- 2020
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10. Oxetane Promise Delivered: Discovery of Long-Acting IDO1 Inhibitors Suitable for Q3W Oral or Parenteral Dosing
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Derun Li, David L. Sloman, Abdelghani Achab, Hua Zhou, Meredeth A. McGowan, Catherine White, Craig Gibeau, Hongjun Zhang, Qinglin Pu, Indu Bharathan, Brett Hopkins, Kun Liu, Heidi Ferguson, Xavier Fradera, Charles A. Lesburg, Theodore A. Martinot, Ji Qi, Zhiguo J. Song, Jingjun Yin, Huangguang Zhang, Licheng Song, Baoqiang Wan, Suzanne DAddio, Nicolas Solban, J. Richard Miller, Beata Zamlynny, Alan Bass, Elizabeth Freeland, Bridget Ykoruk, Catherine Hilliard, Jude Ferraro, Jin Zhai, Ian Knemeyer, Karin M. Otte, Stella Vincent, Nunzio Sciammetta, Alexander Pasternak, David Jonathan Bennett, and Yongxin Han
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Cyclization ,Ethers, Cyclic ,Drug Discovery ,Molecular Medicine ,Indoleamine-Pyrrole 2,3,-Dioxygenase ,Enzyme Inhibitors ,Amides - Abstract
3,3-Disubstituted oxetanes have been utilized as bioisosteres for gem-dimethyl and cyclobutane functionalities. We report the discovery of a novel class of oxetane indole-amine 2,3-dioxygenase (IDO1) inhibitors suitable for Q3W (once every 3 weeks) oral and parenteral dosing. A diamide class of IDO inhibitors was discovered through an automated ligand identification system (ALIS). Installation of an oxetane and fluorophenyl dramatically improved the potency. Identification of a biaryl moiety as an unconventional amide isostere addressed the metabolic liability of amide hydrolysis. Metabolism identification (Met-ID)-guided target design and the introduction of polarity resulted in the discovery of potent IDO inhibitors with excellent pharmacokinetic (PK) profiles in multiple species. To enable rapid synthesis of the key oxetane intermediate, a novel oxetane ring cyclization was also developed, as well as optimization of a literature route on kg scale. These IDO inhibitors may enable unambiguous proof-of-concept testing for the IDO1 inhibition mechanism for oncology.
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- 2022
11. Discovery of MK-8153, a Potent and Selective ROMK Inhibitor and Novel Diuretic/Natriuretic
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Xin Gu, Brande Thomas-Fowlkes, Dorothy Levorse, Harry R. Chobanian, Timothy Cutarelli, Alexander Pasternak, Adam B. Weinglass, Ian W. Davies, Martin Koehler, Michael Margulis, Fa-Xiang Ding, Joel B. Yudkovitz, Jinlong Jiang, Haifeng Tang, Lee-Yuh Pai, Barbara Pio, Shuzhi Dong, Mengwei Hu, Kathleen A. Sullivan, Jack Gibson, Thomas Bateman, Koppara Samuel, Xiaoyan Zhou, Caryn Hampton, Reynalda deJesus, Kevin Houle, and Emma R. Parmee
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Male ,medicine.medical_treatment ,Diuresis ,Action Potentials ,Blood Pressure ,Pharmacology ,01 natural sciences ,Piperazines ,Natriuresis ,Excretion ,03 medical and health sciences ,Dogs ,Rats, Inbred SHR ,Drug Discovery ,medicine ,Potassium Channel Blockers ,Animals ,Humans ,Dosing ,Potassium Channels, Inwardly Rectifying ,Diuretics ,030304 developmental biology ,Benzofurans ,0303 health sciences ,Chemistry ,Furosemide ,Haplorhini ,medicine.disease ,0104 chemical sciences ,Rats ,010404 medicinal & biomolecular chemistry ,Heart failure ,ROMK ,Potassium ,Molecular Medicine ,Natriuretic Agents ,Diuretic ,medicine.drug ,Half-Life - Abstract
A renal outer medullary potassium channel (ROMK, Kir1.1) is a putative drug target for a novel class of diuretics with potential for treating hypertension and heart failure. Our first disclosed clinical ROMK compound, 2 (MK-7145), demonstrated robust diuresis, natriuresis, and blood pressure lowering in preclinical models, with reduced urinary potassium excretion compared to the standard of care diuretics. However, 2 projected to a short human half-life (∼5 h) that could necessitate more frequent than once a day dosing. In addition, a short half-life would confer a high peak-to-trough ratio which could evoke an excessive peak diuretic effect, a common liability associated with loop diuretics such as furosemide. This report describes the discovery of a new ROMK inhibitor 22e (MK-8153), with a longer projected human half-life (∼14 h), which should lead to a reduced peak-to-trough ratio, potentially extrapolating to more extended and better tolerated diuretic effects.
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- 2021
12. Carbamate and N-Pyrimidine Mitigate Amide Hydrolysis: Structure-Based Drug Design of Tetrahydroquinoline IDO1 Inhibitors
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Karin M. Otte, Yongxin Han, Pravien Abeywickrema, Elliott B. Nickbarg, Brett A. Hopkins, Patrick J. Curran, Kun Liu, Chad Chamberlin, Christine Andrews, Mangeng Cheng, Stella H. Vincent, Omar Mabrouk, Matthew Richards, Charles A. Lesburg, Prasanthi Geda, Peter Saradjian, Heidi Ferguson, Alfred Lammens, Sulagna Sanyal, Yongqi Deng, Nunzio Sciammetta, Nadya Smotrov, Ian Knemeyer, Jongwon Lim, Xavier Fradera, J. Richard Miller, Indu Bharathan, Hongjun Zhang, David Jonathan Bennett, Abdelghani Achab, Derun Li, Qinglin Pu, Theodore A. Martinot, Wensheng Yu, Alexander Pasternak, Hua Zhou, Xuelei Song, Peter Spacciapoli, Ryan D. Cohen, and Amy C. Doty
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Carbamate ,Pyrimidine ,010405 organic chemistry ,medicine.medical_treatment ,Metabolite ,Organic Chemistry ,Ligand (biochemistry) ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,Hydrolysis ,chemistry ,Amide ,Drug Discovery ,medicine ,Potency ,Lead compound - Abstract
[Image: see text] Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as an attractive target for cancer immunotherapy. An automated ligand identification system screen afforded the tetrahydroquinoline class of novel IDO1 inhibitors. Potency and pharmacokinetic (PK) were key issues with this class of compounds. Structure-based drug design and strategic incorporation of polarity enabled the rapid improvement on potency, solubility, and oxidative metabolic stability. Metabolite identification studies revealed that amide hydrolysis in the D-pocket was the key clearance mechanism for this class. Strategic survey of amide isosteres revealed that carbamates and N-pyrimidines, which maintained exquisite potencies, mitigated the amide hydrolysis issue and led to an improved rat PK profile. The lead compound 28 is a potent IDO1 inhibitor, with clean off-target profiles and the potential for quaque die dosing in humans.
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- 2021
13. The therapeutic potential of targeting the Kir1.1 (renal outer medullary K+) channel
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Birgit T. Priest and Alexander Pasternak
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0301 basic medicine ,Pharmacology ,Kidney ,business.industry ,Inward-rectifier potassium ion channel ,Sodium channel ,Potassium ,chemistry.chemical_element ,medicine.disease ,Potassium channel ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,Blood pressure ,chemistry ,Heart failure ,Drug Discovery ,medicine ,Molecular Medicine ,Efflux ,business - Abstract
Kir1.1 (renal outer medullary K+) channels are potassium channels expressed almost exclusively in the kidney and play a role in the body's electrolyte and water balance. Potassium efflux through Kir1.1 compliments the role of transporters and sodium channels that are the targets of known diuretics. Consequently, loss-of-function mutations in men and rodents are associated with salt wasting and low blood pressure. On this basis, Kir1.1 inhibitors may have value in the treatment of hypertension and heart failure. Efforts to develop small molecule Kir1.1 inhibitors produced MK-7145, which entered into clinical trials. The present manuscript describes the structure–activity relationships associated with this scaffold alongside other preclinical Kir1.1 blockers.
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- 2017
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14. Improvement of hERG-ROMK index of spirocyclic ROMK inhibitors through scaffold optimization and incorporation of novel pharmacophores
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Haifeng Tang, Zack Zhiqiang Guo, Lee-Yuh Pai, Adam B. Weinglass, Xin Gu, Shuzhi Dong, Alexander Pasternak, Yang Yu, Kathleen A. Sullivan, Mengwei Hu, Kelsey VanGelder, Gloria J. Zingaro, Sophie Roy, Jessica Liu, Qinghong Fu, Birgit T. Priest, Michael Margulis, Brande Thomas-Fowlkes, Pierre Morissette, Robin E. Haimbach, Zhicai Wu, Juliann Ehrhart, Karen Owens, Caryn Hampton, Zhi-Cai Shi, Jessica Frie, Ron Ferguson, Shiyao Xu, and Vincent Tong
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0301 basic medicine ,ERG1 Potassium Channel ,Scaffold ,Clinical Biochemistry ,hERG ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,Structure-Activity Relationship ,03 medical and health sciences ,Dogs ,0302 clinical medicine ,Thiadiazoles ,In vivo ,Rats, Inbred SHR ,Drug Discovery ,Potassium Channel Blockers ,medicine ,Animals ,Structure–activity relationship ,Spiro Compounds ,Potassium Channels, Inwardly Rectifying ,Molecular Biology ,biology ,Chemistry ,Organic Chemistry ,Potassium channel blocker ,Rats ,Disease Models, Animal ,Pyrimidines ,030104 developmental biology ,030220 oncology & carcinogenesis ,Hypertension ,ROMK ,biology.protein ,Molecular Medicine ,Pharmacophore ,Half-Life ,medicine.drug - Abstract
SAR in the previously described spirocyclic ROMK inhibitor series was further evolved from lead 4 by modification of the spirocyclic core and identification of novel right-side pharmacophores. In this process, it was discovered that the spiropyrrolidinone core with the carbonyl group α to the spirocenter was preferred for potent ROMK activity. Efforts aimed at decreasing hERG affinity within the series led to the discovery of multiple novel right-hand pharmacophores including 3-methoxythiadiazole, 2-methoxypyrimidine, and pyridazinone. The most promising candidate is pyridazinone analog 32 that showed an improved functional hERG/ROMK potency ratio and preclinical PK profile. In vivo evaluation of 32 demonstrated blood pressure lowering effects in the spontaneously hypertensive rat model.
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- 2017
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15. The design and synthesis of novel spirocyclic heterocyclic sulfone ROMK inhibitors as diuretics
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Lee-Yuh Pai, Aaron Corona, Harry R. Chobanian, John P. Felix, Matthew J. Clements, Karen Owens, Haifeng Tang, Brande Thomas-Fowlkes, Kathleen A. Sullivan, Alexander Pasternak, Caryn Hampton, Jessica Frie, Vincent Tong, Ron Ferguson, Jessica Liu, Birgit T. Priest, Barbara Pio, Yan Guo, Elizabeth Joshi, Nardos Teumelsan, Ling Xu, Martin Köhler, Joseph M. Metzger, Zach Guo, and Kevin M. Maloney
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0301 basic medicine ,Stereochemistry ,medicine.medical_treatment ,Clinical Biochemistry ,hERG ,Pharmaceutical Science ,Diuresis ,Biochemistry ,Natriuresis ,Sulfone ,03 medical and health sciences ,chemistry.chemical_compound ,Heterocyclic Compounds ,Rats, Inbred SHR ,Drug Discovery ,medicine ,Animals ,Moiety ,Organic chemistry ,Sulfones ,Enzyme Inhibitors ,Potassium Channels, Inwardly Rectifying ,Diuretics ,Molecular Biology ,biology ,Chemistry ,Organic Chemistry ,Rats ,030104 developmental biology ,Drug Design ,ROMK ,biology.protein ,Molecular Medicine ,Diuretic ,Selectivity - Abstract
A spirocyclic class of ROMK inhibitors was developed containing a structurally diverse heterocyclic sulfone moiety and spirocyclic core starting from lead 1. These compounds not only displayed exquisite ROMK potency but significantly improved selectivity over hERG. The lead compounds were found to have favorable pharmacokinetic properties and displayed robust diuretic, natriuretic and blood pressure lowering effects in spontaneously hypertensive rats.
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- 2017
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16. Pharmacological inhibition of hematopoietic progenitor kinase 1 positively regulates T-cell function
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Steven Wells, Jason Laskey, Robbie L. McLeod, Brian M. Lacey, Joey L. Methot, Alexander Pasternak, Yun Wang, Mark Bittinger, Kelvin Xi Zhang, Sheila Ranganath, Haiyan Xu, Zangwei Xu, and Peter Georgiev
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Adenosine ,Physiology ,medicine.medical_treatment ,T-Lymphocytes ,Cancer Treatment ,Glycobiology ,Lymphocyte Activation ,Biochemistry ,White Blood Cells ,Cancer immunotherapy ,Interferon ,Animal Cells ,Immune Physiology ,Medicine and Health Sciences ,Cytotoxic T cell ,Innate Immune System ,Multidisciplinary ,Chemistry ,T Cells ,Nucleosides ,Glycosylamines ,medicine.anatomical_structure ,Oncology ,Cytokines ,Medicine ,Female ,Immunotherapy ,Signal transduction ,Cellular Types ,medicine.drug ,Research Article ,T cell ,Immune Cells ,Science ,Immunology ,Cytotoxic T cells ,Protein Serine-Threonine Kinases ,Research and Analysis Methods ,Cancer Immunotherapy ,Immune system ,medicine ,Animals ,Kinase activity ,Molecular Biology Techniques ,Protein Kinase Inhibitors ,Molecular Biology ,Secretion ,Blood Cells ,Biology and Life Sciences ,Cell Biology ,Molecular Development ,Mice, Inbred C57BL ,Immune System ,Cancer research ,Clinical Immunology ,Clinical Medicine ,Physiological Processes ,Developmental Biology ,Cloning - Abstract
Hematopoietic progenitor kinase 1 (HPK1), a hematopoietic cell-specific Ste20-related serine/threonine kinase, is a negative regulator of signal transduction in immune cells, including T cells, B cells, and dendritic cells (DCs). In mice, HPK1 deficiency subverts inhibition of the anti-tumor immune response and is associated with functional augmentation of anti-tumor T cells. We have used a potent, small molecule HPK1 inhibitor, Compound 1, to investigate the effects of pharmacological intervention of HPK1 kinase activity in immune cells. Compound 1 enhanced Th1 cytokine production in T cells and fully reverted immune suppression imposed by the prostaglandin E2(PGE2) and adenosine pathways in human T cells. Moreover, the combination of Compound 1 with pembrolizumab, a humanized monoclonal antibody against the programmed cell death protein 1 (PD-1), demonstrated a synergistic effect, resulting in enhanced interferon (IFN)-γ production. Collectively, our results suggest that blocking HPK1 kinase activity with small molecule inhibitors alone or in combination with checkpoint blockade may be an attractive approach for the immunotherapy of cancer.
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- 2020
17. Discovery of a potent and selective ROMK inhibitor with improved pharmacokinetic properties based on an octahydropyrazino[2,1-c][1,4]oxazine scaffold
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Shawn P. Walsh, Lee-Yuh Pai, Yuping Zhu, John P. Felix, Caryn Hampton, Xiaoyan Zhou, Melba Hernandez, Brande Thomas-Fowlkes, Richard M. Brochu, Nardos Teumelsan, Gregory J. Kaczorowski, Emma R. Parmee, Maria L. Garcia, Alexander Pasternak, Jinlong Jiang, Sookhee Ha, Sophie Roy, Kathleen A. Sullivan, Haifeng Tang, Lihu Yang, Karen Owens, Reynalda K. de Jesus, Xin Gu, Birgit T. Priest, Barbara Pio, Fa-Xiang Ding, Andrew M. Swensen, Magdalena Alonso-Galicia, Aurash Shahripour, Juliann Ehrhart, and Timothy Bailey
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0301 basic medicine ,QTC PROLONGATION ,Clinical Biochemistry ,hERG ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,Dog model ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,Dogs ,0302 clinical medicine ,Transcriptional Regulator ERG ,Pharmacokinetics ,In vivo ,Oxazines ,Drug Discovery ,Animals ,Humans ,Potassium Channels, Inwardly Rectifying ,Molecular Biology ,Heart Failure ,biology ,Chemistry ,Organic Chemistry ,Macaca mulatta ,Small molecule ,Diuresis ,Piperazine ,030104 developmental biology ,030220 oncology & carcinogenesis ,Hypertension ,ROMK ,biology.protein ,Molecular Medicine - Abstract
Following the discovery of small molecule acyl piperazine ROMK inhibitors, the acyl octahydropyrazino[2,1-c][1,4]oxazine series was identified. This series displays improved ROMK/hERG selectivity, and as a consequence, the resulting ROMK inhibitors do not evoke QTc prolongation in an in vivo cardiovascular dog model. Further efforts in this series led to the discovery of analogs with improved pharmacokinetic profiles. This new series also retained comparable ROMK potency compared to earlier leads.
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- 2016
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18. Discovery of MK-7145, an Oral Small Molecule ROMK Inhibitor for the Treatment of Hypertension and Heart Failure
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Michael J. Forrest, John P. Felix, Lee-Yuh Pai, Melba Hernandez, Yuping Zhu, Aaron Corona, Joseph M. Metzger, Gregory J. Kaczorowski, Nardos Teumelsan, Lihu Yang, Karen Owens, Timothy Bailey, Caryn Hampton, Vincent Tong, Alexander Pasternak, Brande Thomas-Fowlkes, Shawn P. Walsh, Emma R. Parmee, Haifeng Tang, Richard M. Brochu, Maria L. Garcia, Xiaoyan Zhou, Magdalena Alonso-Galicia, Sophie Roy, Birgit T. Priest, Andrew M. Swensen, and Aurash Shahripour
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0301 basic medicine ,medicine.medical_specialty ,Kidney ,biology ,Chemistry ,Organic Chemistry ,hERG ,Diuresis ,Nephron ,Pharmacology ,Biochemistry ,Natriuresis ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Internal medicine ,Drug Discovery ,medicine ,biology.protein ,Loop of Henle ,ROMK ,Thiazide ,medicine.drug - Abstract
ROMK, the renal outer medullary potassium channel, is involved in potassium recycling at the thick ascending loop of Henle and potassium secretion at the cortical collecting duct in the kidney nephron. Because of this dual site of action, selective inhibitors of ROMK are expected to represent a new class of diuretics/natriuretics with superior efficacy and reduced urinary loss of potassium compared to standard-of-care loop and thiazide diuretics. Following our earlier work, this communication will detail subsequent medicinal chemistry endeavors to further improve lead selectivity against the hERG channel and preclinical pharmacokinetic properties. Pharmacological assessment of highlighted inhibitors will be described, including pharmacodynamic studies in both an acute rat diuresis/natriuresis model and a subchronic blood pressure model in spontaneous hypertensive rats. These proof-of-biology studies established for the first time that the human and rodent genetics accurately predict the in vivo pharmacology of ROMK inhibitors and supported identification of the first small molecule ROMK inhibitor clinical candidate, MK-7145.
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- 2016
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19. Abstract 427: Inhibition of Myocardial Romk Channels Blocks Ischemic Preconditioning Induced Cardio-protection
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John W. Kyle, Brandi A Weidmeyer, Jonathan C. Makielski, Elizabeth M. McNally, Alexander Pasternak, Mohun Ramratnam, Warren Linnerooth, Nihal Ahmad, and Emily D Lacount
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Physiology ,Chemistry ,Protein subunit ,RENAL OUTER-MEDULLARY POTASSIUM CHANNEL ,Mitochondrion ,Pharmacology ,medicine.disease ,Katp channels ,Cardio protection ,medicine ,ROMK ,Ischemic preconditioning ,cardiovascular diseases ,Cardiology and Cardiovascular Medicine ,Reperfusion injury - Abstract
Background: Prior evidence has shown that the renal outer medullary potassium channel (Kir 1.1 or ROMK) may be the pore forming subunit of the mitochondrial KATP channel (mitoKATP). However, it is unknown if ROMK inhibition affects myocardial function after ischemia reperfusion injury or cardio-protection from ischemic preconditioning. Methods: C57/BL6J mice were subjected to ex vivo ischemia (45 min) and then reperfusion (60 min) with or without ischemic preconditioning (3 cycles of 3 min). Mice were treated throughout the protocol with either 5 μM of compound A, a potent ROMK inhibitor, or vehicle, in a modified Krebs Henseliet buffer. Results: WT mice hearts subjected to ischemia reperfusion injury and perfused with 5 μM compound A recovered 73% of baseline left ventricular developed pressure (LVDP) while mouse hearts perfused with vehicle recovered 50% of baseline LVDP (P=0.07, N=3). Infarct size was not significantly different between hearts perfused with 5 μM compound A or vehicle (32% ± 7% vs. 46% ± 10%, P =0.18, N=3). In vehicle perfused mice, IPC significantly improved % recovery of LVDP (IPC 87% ± 9% vs. no IPC 50% ± 7%, P =0.014, N=3) and infarct size (IPC 22% ± 4% vs no IPC 46% ± 11%, P =0.02, N=3). However, IPC did not improve % recovery of LVDP (IPC 69% ± 6% vs no IPC 73% ± 4%, P =0.33, N=3) or infarct size (IPC 46% ± 14% vs no IPC 32% ± 7%, P =0.22, N=3) in mouse hearts perfused with compound A. Conclusions: Myocardial ROMK inhibition does not increase IR injury in an ex vivo mouse preparation, but does block cardio-protection from IPC further supporting ROMK as the potential pore forming channel of mitoKATP.
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- 2018
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20. Discovery of a Potent and Selective ROMK Inhibitor with Pharmacokinetic Properties Suitable for Preclinical Evaluation
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Lee-Yuh Pai, Yuping Zhu, Richard Visconti, Xiaoyan Zhou, John P. Felix, Melba Hernandez, Jing Chen, Michael Margulis, Nardos Teumelsan, Sophie Roy, Kathleen A. Sullivan, Jessica Liu, Joseph M. Metzger, Aaron Corona, Gregory J. Kaczorowski, Maria L. Garcia, Lihu Yang, Shawn P. Walsh, Birgit T. Priest, Alexander Pasternak, Caryn Hampton, Emma R. Parmee, Vincent Tong, Brande Thomas-Fowlkes, Haifeng Tang, Magdalena Alonso-Galicia, Kashmira Shah, Michael J. Forrest, Richard M. Brochu, Ross Bentley, Sookhee Ha, Karen Owens, Aurash Shahripour, Andrew M. Swensen, Jessica Frie, Adam B. Weinglass, and Timothy Bailey
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Pharmacokinetics ,Chemistry ,Pharmacodynamics ,Organic Chemistry ,Drug Discovery ,ROMK ,Pharmacology ,Biochemistry - Abstract
A new subseries of ROMK inhibitors exemplified by 28 has been developed from the initial screening hit 1. The excellent selectivity for ROMK inhibition over related ion channels and pharmacokinetic properties across preclinical species support further preclinical evaluation of 28 as a new mechanism diuretic. Robust pharmacodynamic effects in both SD rats and dogs have been demonstrated.
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- 2015
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21. Abstract 068: Impact of Renal Outer Medullary Potassium Channel Inhibition on Afferent Arteriolar Tone in Rats With Type 1 Diabetes
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Pamela K Carmines, Xiaoyan Zhou, Maya Dajee, Kathleen A Sullivan, Shawn P Walsh, and Alexander Pasternak
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Internal Medicine - Abstract
The bee venom toxin tertiapin Q (TPQ) evokes tubuloglomerular feedback-independent afferent arteriolar constriction in kidneys from rats with streptozotocin-induced type 1 diabetes (STZ rats). Because TPQ inhibits both Kir1.1 and Kir3.x channels, the contribution of Kir1.1 (renal outer medullary potassium channel; ROMK) to afferent arteriolar tone in diabetes remains uncertain. To test the hypothesis that Kir1.1 exerts a tonic dilator influence on the afferent arteriole during diabetes, we compared afferent arteriolar responses to the novel, small molecule Kir1.1-selective inhibitor Compound C (CmpdC) to those evoked by TPQ. The ex vivo blood-perfused juxtamedullary nephron technique was used to monitor afferent arteriolar lumen diameter before and during exposure to TPQ (1-100 nM) or CmpdC (10 nM-10 μM). Neither agent altered afferent arteriolar diameter in kidneys from normal rats. In kidneys from STZ rats (blood glucose concentration = 465 ± 12 mg/dl), baseline afferent arteriolar diameter averaged 22.9 ± 0.6 μm ( n = 30). Both TPQ and CmpdC evoked concentration-dependent arteriolar constriction, with 100 nM TPQ decreasing diameter by 2.5 ± 0.6 μm ( n = 6; P < 0.001 vs baseline) and 100 nM CmpdC reducing diameter by 1.7 ± 0.6 μm ( n = 10; P = 0.004 vs baseline; P = 0.42 vs 100 nM TPQ). During subsequent exposure to 10 μM CmpdC, arteriolar diameter was 2.1 ± 0.8 μm below baseline. The similar effects of the Kir1.1/3.x inhibitor TPQ and the Kir1.1-selective inhibitor CmpdC on arteriolar diameter in kidneys from STZ rats support the contention that Kir1.1 exerts a tonic afferent arteriolar dilator influence during type 1 diabetes. In follow-up studies, the NKCC inhibitor furosemide (30-300 μM) administered via the bath did not alter afferent arteriolar diameter in kidneys from STZ rats; however, prior exposure to furosemide prevented the vasoconstrictor response to 100 nM CmpdC (Δ diameter = -0.4 ± 0.3 μm; n = 8) although the response to 100 nM TPQ remained intact (Δ diameter = -2.6 ± 1.3 μm; n = 6). The differential impact of furosemide pretreatment on arteriolar responses to TPQ and CmpdC suggests a complex interplay between the furosemide-sensitive vascular NKCC1 and tubular NKCC2, and the TPQ- and CmpdC-sensitive Kir1.1 expressed in both the vasculature and tubule.
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- 2017
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22. Discovery of a novel sub-class of ROMK channel inhibitors typified by 5-(2-(4-(2-(4-(1H-Tetrazol-1-yl)phenyl)acetyl)piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one
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Yan Yan, Richard M. Brochu, Maria L. Garcia, Lihu Yang, Sophie Roy, Gregory J. Kaczorowski, Reynald K. de Jesus, Birgit T. Priest, Xiaoyan Zhou, Lee-Yuh Pai, Shawn P. Walsh, Yuping Zhu, Karen Owens, Caryn Hampton, Timothy Bailey, Andrew M. Swensen, Brande Thomas-Fowlkes, Magdalena Alonso-Galicia, John P. Felix, Melba Hernandez, Alexander Pasternak, and Haifeng Tang
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Natriuretic Agents ,Isobenzofuran ,Stereochemistry ,Clinical Biochemistry ,hERG ,Tetrazoles ,Pharmaceutical Science ,Biochemistry ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,In vivo ,Drug Discovery ,Animals ,Humans ,Potassium Channels, Inwardly Rectifying ,Molecular Biology ,Benzofurans ,biology ,Chemistry ,Organic Chemistry ,Small molecule ,Ether-A-Go-Go Potassium Channels ,Diuresis ,Rats ,ROMK ,biology.protein ,Molecular Medicine - Abstract
A sub-class of distinct small molecule ROMK inhibitors were developed from the original lead 1. Medicinal chemistry endeavors led to novel ROMK inhibitors with good ROMK functional potency and improved hERG selectivity. Two of the described ROMK inhibitors were characterized for the first in vivo proof-of-concept biology studies, and results from an acute rat diuresis model confirmed the hypothesis that ROMK inhibitors represent new mechanism diuretic and natriuretic agents.
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- 2013
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23. Inhibition of ROMK blocks macula densa tubuloglomerular feedback yet causes renal vasoconstriction in anesthetized rats
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Xiaoyan Zhou, Shawn P. Walsh, William J. Welch, Kathleen A. Sullivan, Magali Araujo, Alexander Pasternak, and Christopher S. Wilcox
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Male ,medicine.medical_specialty ,Physiology ,Kidney Glomerulus ,030232 urology & nephrology ,Natriuresis ,030204 cardiovascular system & hematology ,Anesthesia, General ,Feedback ,Renal Circulation ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Sodium Potassium Chloride Symporter Inhibitors ,Furosemide ,Internal medicine ,medicine ,Loop of Henle ,Hydrostatic Pressure ,Potassium Channel Blockers ,Animals ,Vasoconstrictor Agents ,Potassium Channels, Inwardly Rectifying ,Diuretics ,Tubuloglomerular feedback ,Solute Carrier Family 12, Member 1 ,Dose-Response Relationship, Drug ,Reabsorption ,Chemistry ,Potassium channel ,medicine.anatomical_structure ,Endocrinology ,Kidney Tubules ,Vasoconstriction ,Models, Animal ,ROMK ,Potassium ,Macula densa ,Calcium ,Vascular Resistance ,Cotransporter ,medicine.drug ,Glomerular Filtration Rate ,Signal Transduction - Abstract
The Na+-K+-2Cl−cotransporter (NKCC2) on the loop of Henle is the site of action of furosemide. Because outer medullary potassium channel (ROMK) inhibitors prevent reabsorption by NKCC2, we tested the hypothesis that ROMK inhibition with a novel selective ROMK inhibitor (compound C) blocks tubuloglomerular feedback (TGF) and reduces vascular resistance. Loop perfusion of either ROMK inhibitor or furosemide caused dose-dependent blunting of TGF, but the response to furosemide was 10-fold more sensitive (IC50 = 10−6M for furosemide and IC50= 10−5M for compound C). During systemic infusion, both diuretics inhibited TGF, but ROMK inhibitor was 10-fold more sensitive (compound C: 63% inhibition; furosemide: 32% inhibition). Despite blockade of TGF, 1 h of constant systemic infusion of both diuretics reduced the glomerular filtration rate (GFR) and renal blood flow (RBF) by 40–60% and increased renal vascular resistance (RVR) by 100–200%. Neither diuretic altered blood pressure or hematocrit. Proximal tubule hydrostatic pressures (PPT) increased transiently with both diuretics (compound C: 56% increase; furosemide: 70% increase) but returned to baseline. ROMK inhibitor caused more natriuresis (3,400 vs. 1,600% increase) and calciuresis (1,200 vs. 800% increase) but less kaliuresis (33 vs. 167% increase) than furosemide. In conclusion, blockade of ROMK or Na+-K+-2Cl−transport inhibits TGF yet increases renal vascular resistance. The renal vasoconstriction was independent of volume depletion, blood pressure, TGF, or PPT.
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- 2016
24. Chronic Inhibition of Renal Outer Medullary Potassium Channel Not Only Prevented but Also Reversed Development of Hypertension and End-Organ Damage in Dahl Salt-Sensitive Rats
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Xiaoyan Zhou, Maya Dajee, Michael J. Forrest, Gail Forrest, Sloan Stribling, Andra S. Stevenson, Shawn P. Walsh, Kathleen A. Sullivan, Yonghua Zhu, Wanda Sharif-Rodriguez, Daphne Szeto, Alexander Pasternak, Yuchen Zhou, and Olga Urosevic-Price
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0301 basic medicine ,medicine.medical_specialty ,Medullary cavity ,End organ damage ,Potassium ,chemistry.chemical_element ,Blood Pressure ,Pharmacology ,03 medical and health sciences ,Hydrochlorothiazide ,Internal medicine ,Internal Medicine ,medicine ,Loop of Henle ,Animals ,Potassium Channels, Inwardly Rectifying ,Kidney Medulla ,Rats, Inbred Dahl ,Renal sodium reabsorption ,business.industry ,Acute Kidney Injury ,medicine.disease ,Rats ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Hypertension ,ROMK ,Cotransporter ,business ,Biomarkers ,medicine.drug ,Glomerular Filtration Rate - Abstract
The renal outer medullary potassium (ROMK) channel mediates potassium recycling and facilitates sodium reabsorption through the Na + /K + /2Cl − cotransporter in the loop of Henle and potassium secretion at the cortical collecting duct. Evidence from the phenotype of humans and rodents with functional ROMK deficiency supports the contention that selective ROMK inhibitors (ROMKi) will represent a novel diuretic with potential of therapeutic benefit for hypertension. ROMKi have recently been synthesized by Merck & Co, Inc. The present studies were designed to examine the effects of ROMKi B on systemic hemodynamics, renal function and structure, and vascular function in Dahl salt-sensitive rats. Four experimental groups—control, high-salt diet alone; ROMKi B 3 mg·kg − 1 ·d − 1 ; ROMKi B 10 mg·kg − 1 ·d − 1 ; and hydrochlorothiazide 25 mg·kg − 1 ·d − 1 —were included in prophylactic (from week 1 to week 9 on high-salt diet) and therapeutic studies (from week 5 to week 9 on high-salt diet), respectively. ROMKi B produced sustained blood pressure reduction and improved renal and vascular function and histological alterations induced by a high-salt diet. ROMKi B was superior to hydrochlorothiazide at reducing blood pressure. Furthermore, ROMKi B provided beneficial effects on both the plasma lipid profile and bone mineral density. Chronic ROMK inhibition not only prevented but also reversed the development of hypertension and end-organ damage in Dahl salt-sensitive rats. Our findings suggest a potential utility of ROMKi B as a novel antihypertensive agent, particularly for the treatment of the salt-sensitive hypertension patient population.
- Published
- 2016
25. The Renal Outer Medullary Potassium Channel Inhibitor, MK-7145, Lowers Blood Pressure, and Manifests Features of Bartter's Syndrome Type II Phenotype
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Haifeng Tang, Kashmira Shah, Maria L. Garcia, Alexander Pasternak, Magdalena Alonso-Galicia, Brande Thomas-Fowlkes, Cordelia Rasa, Joseph M. Metzger, Sophie Roy, Lee-Yuh Pai, Jessica Liu, Olga Price, Vince Tong, Birgit T. Priest, Gregory J. Kaczorowski, James D. Ormes, Charles Gill, Aaron Corona, John P. Felix, Jianying Xiao, Kathleen A. Sullivan, Karen Owens, Caryn Hampton, Xiaoyan Zhou, and Martin Köhler
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0301 basic medicine ,Male ,medicine.medical_specialty ,Diuresis ,Tetrazoles ,Blood Pressure ,Pharmacology ,Bartter syndrome ,Piperazines ,Natriuresis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Dogs ,Internal medicine ,medicine ,Potassium Channel Blockers ,Animals ,Humans ,Potassium Channels, Inwardly Rectifying ,Benzofurans ,Aldosterone ,Dose-Response Relationship, Drug ,Chemistry ,Biphenyl Compounds ,Bartter Syndrome ,Potassium channel blocker ,Drug Synergism ,medicine.disease ,Rats ,Bartter's syndrome ,030104 developmental biology ,Endocrinology ,HEK293 Cells ,Hydrochlorothiazide ,Phenotype ,030220 oncology & carcinogenesis ,Kaliuresis ,ROMK ,Molecular Medicine ,Benzimidazoles ,Female ,medicine.drug - Abstract
The renal outer medullary potassium (ROMK) channel, located at the apical surface of epithelial cells in the thick ascending loop of Henle and cortical collecting duct, contributes to salt reabsorption and potassium secretion, and represents a target for the development of new mechanism of action diuretics. This idea is supported by the phenotype of antenatal Bartter's syndrome type II associated with loss-of-function mutations in the human ROMK channel, as well as, by cardiovascular studies of heterozygous carriers of channel mutations associated with type II Bartter's syndrome. Although the pharmacology of ROMK channels is still being developed, channel inhibitors have been identified and shown to cause natriuresis and diuresis, in the absence of any significant kaliuresis, on acute oral dosing to rats or dogs. Improvements in potency and selectivity have led to the discovery of MK-7145 [5,5'-((1R,1'R)-piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl))bis(4-methylisobenzofuran-1(3H)-one)], a potential clinical development candidate. In spontaneously hypertensive rats, oral dosing of MK-7145 causes dose-dependent lowering of blood pressure that is maintained during the entire treatment period, and that displays additive/synergistic effects when administered in combination with hydrochlorothiazide or candesartan, respectively. Acute or chronic oral administration of MK-7145 to normotensive dogs led to dose-dependent diuresis and natriuresis, without any significant urinary potassium losses or changes in plasma electrolyte levels. Elevations in bicarbonate and aldosterone were found after 6 days of dosing. These data indicate that pharmacological inhibition of ROMK has potential as a new mechanism for the treatment of hypertension and/or congestive heart failure. In addition, Bartter's syndrome type II features are manifested on exposure to ROMK inhibitors.
- Published
- 2016
26. The Inwardly Rectifying Potassium Channel Kir1.1: Development of Functional Assays to Identify and Characterize Channel Inhibitors
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John P. Felix, Chou J. Liu, Magdalena Alonso-Galicia, Kelli Solly, Maria L. Garcia, Laszlo Kiss, Birgit T. Priest, Martin Köhler, Richard M. Brochu, Timothy Bailey, Gregory J. Kaczorowski, Alexander Pasternak, and Haifeng Tang
- Subjects
medicine.medical_specialty ,Potassium ,chemistry.chemical_element ,CHO Cells ,Pharmacology ,Madin Darby Canine Kidney Cells ,Cricetulus ,Dogs ,Cricetinae ,Internal medicine ,Drug Discovery ,Potassium Channel Blockers ,medicine ,Animals ,Humans ,Potassium Channels, Inwardly Rectifying ,Thallium ,Kidney ,Reabsorption ,Molecular Pharmacology ,Potassium channel ,Rats ,Blood pressure ,medicine.anatomical_structure ,Endocrinology ,chemistry ,ROMK ,Molecular Medicine ,Flux (metabolism) - Abstract
The renal outer medullary potassium (ROMK) channel is a member of the inwardly rectifying family of potassium (Kir) channels. ROMK (Kir1.1) is predominantly expressed in kidney where it plays a major role in the salt reabsorption process. Loss-of-function mutations in the human Kir1.1 channel are associated with antenatal Bartter's syndrome type II, a life-threatening salt and water balance disorder. Heterozygous carriers of Kir1.1 mutations associated with antenatal Bartter's syndrome have reduced blood pressure and a decreased risk of developing hypertension by age 60. These data suggest that Kir1.1 inhibitors could represent novel diuretics for the treatment of hypertension. Because little is known about the molecular pharmacology of Kir1.1 channels, assays that provide a robust, reliable readout of channel activity-while operating in high-capacity mode-are needed. In the present study, we describe high-capacity, 384- and 1,536-well plate, functional thallium flux, and IonWorks electrophysiology assays for the Kir1.1 channel that fulfill these criteria. In addition, 96-well (86)Rb(+) flux assays were established that can operate in the presence of 100% serum, and can provide an indication of the effect of a serum shift on compound potencies. The ability to grow Madin-Darby canine kidney cells expressing Kir1.1 in Transwell supports provides a polarized cell system that can be used to study the mechanism of Kir1.1 inhibition by different agents. All these functional Kir1.1 assays together can play an important role in supporting different aspects of drug development efforts during lead identification and/or optimization.
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- 2012
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27. CCR2 Antagonists
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Mary, Struthers and Alexander, Pasternak
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Receptors, CCR2 ,Anti-Inflammatory Agents, Non-Steroidal ,Drug Discovery ,Molecular Conformation ,Animals ,Humans ,Stereoisomerism ,General Medicine ,Ligands - Abstract
Inhibition of CCR2 has been considered as a target for multiple therapeutic diseases including autoimmune disease, atherosclerosis, pain, and metabolic disease, based in part on the critical role this receptor plays on monocyte migration. Numerous companies have reported programs to identify CCR2 antagonists. Common challenges to the development of CCR2 agents have included poor activity at the rodent receptor and selectivity for both other chemokine receptors and ion channels. This review summarizes the rationale for targeting CCR2 in disease, the recent progress in the identification of potent and select CCR2 antagonists, and the current status of clinical trials for CCR2 agents.
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- 2010
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28. Design, synthesis, and structure–activity relationship of novel CCR2 antagonists
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Richard Jiao, Pasquale P. Vicario, Gabor Butora, Shankaran Kothandaraman, Stephen D. Goble, Mary Struthers, Gregori J. Morriello, Julie A. DeMartino, Sander G. Mills, Malcolm MacCoss, Julia M. Ayala, Margaret A. Cascieri, Karla L. Donnely, Changyou Zhou, Lihu Yang, and Alexander Pasternak
- Subjects
CCR2 ,Receptors, CCR2 ,Stereochemistry ,medicine.drug_class ,Chemistry, Pharmaceutical ,Clinical Biochemistry ,Administration, Oral ,Pharmaceutical Science ,Carboxamide ,Biochemistry ,Chemical synthesis ,Rats, Sprague-Dawley ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,chemistry.chemical_compound ,Dogs ,Drug Discovery ,medicine ,Animals ,Humans ,Structure–activity relationship ,Receptor ,Molecular Biology ,Amination ,Molecular Structure ,Chemotaxis ,Organic Chemistry ,Tetrahydropyran ,Macaca mulatta ,Rats ,Models, Chemical ,chemistry ,Design synthesis ,Drug Design ,Molecular Medicine - Abstract
A series of novel 1-aminocyclopentyl-3-carboxyamides incorporating substituted tetrahydropyran moieties have been synthesized and subsequently evaluated for their antagonistic activity against the human CCR2 receptor. Among them analog 59 was found to posses potent antagonistic activity.
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- 2009
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29. Potent heteroarylpiperidine and carboxyphenylpiperidine 1-alkyl-cyclopentane carboxamide CCR2 antagonists
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Julie A. DeMartino, Stephen D. Goble, Mary Struthers, Jerry Di Salvo, Pasquale P. Vicario, Alexander Pasternak, Julia M. Ayala, Sander G. Mills, and Lihu Yang
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Receptors, CCR2 ,medicine.drug_class ,Stereochemistry ,animal diseases ,Clinical Biochemistry ,Pharmaceutical Science ,Carboxamide ,Biochemistry ,Chemical synthesis ,Structure-Activity Relationship ,chemistry.chemical_compound ,Piperidines ,parasitic diseases ,Drug Discovery ,Potassium Channel Blockers ,medicine ,Animals ,Humans ,Moiety ,Cyclopentane ,Molecular Biology ,Alkyl ,chemistry.chemical_classification ,Molecular Structure ,Chemistry ,Ligand binding assay ,Organic Chemistry ,Rats ,Molecular Medicine ,Piperidine ,Selectivity - Abstract
This report describes replacement of the 4-(4-fluorophenyl)piperidine moiety in our CCR2 antagonists with 4-heteroaryl piperidine and 4-(carboxyphenyl)-piperidine subunits. Some of the resulting analogs retained potency in our CCR2 binding assay and had improved selectivity versus the IKr channel; poor selectivity against IKr had been a liability of earlier analogs in this series.
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- 2008
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30. SAR exploration at the C-3 position of tetrahydro-β-carboline sstr3 antagonists
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Janet Kerr, Gary G. Chicchi, Margaret Wu, Cai Li, Shuwen He, Vijay Bhasker G. Reddy, Sharon Tong, William K. Hagmann, Patrick Fitzgerald, Guillermo Fernandez, Andrew D. Howard, Tianying Jian, Zhe Feng, Raman K. Bakshi, Dorina Trusca, Peter H. Dobbelaar, Donald Nelson, Mikhail Reibarkh, Qing Shao, Liangqin Guo, Yun-Ping Zhou, Ravi P. Nargund, Kwei-Lan Tsao, Edward C. Sherer, Stan Mitelman, Pierre Morissette, Maria E. Trujillo, Quang Truong, Zhixiong Ye, James D. Dellureficio, Hongbo Qi, Melissa Lin, Shrenik K. Shah, Sylvia Volksdorf, Jian Liu, Qingmei Hong, Koppara Samuel, Alexander Pasternak, George J. Eiermann, Patricia B. Bunting, Wu Du, and Bei B. Zhang
- Subjects
QTC PROLONGATION ,congenital, hereditary, and neonatal diseases and abnormalities ,Clinical Biochemistry ,hERG ,Pharmaceutical Science ,Pharmacology ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Mice ,Structure-Activity Relationship ,Dogs ,Drug Discovery ,Animals ,Humans ,cardiovascular diseases ,Receptors, Somatostatin ,Molecular Biology ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Antagonist ,0104 chemical sciences ,Rats ,biology.protein ,Molecular Medicine ,Antagonism ,Carbolines - Abstract
MK-4256, a tetrahydro-β-carboline sstr3 antagonist, was discontinued due to a cardiovascular (CV) adverse effect observed in dogs. Additional investigations revealed that the CV liability (QTc prolongation) was caused by the hERG off-target activity of MK-4256 and was not due to sstr3 antagonism. In this Letter, we describe our extensive SAR effort at the C3 position of the tetrahydro-β-carboline structure. This effort resulted in identification of 5-fluoro-pyridin-2-yl as the optimal substituent on the imidazole ring to balance sstr3 activity and the hERG off-target liability.
- Published
- 2015
31. Differentiation of ROMK potency from hERG potency in the phenacetyl piperazine series through heterocycle incorporation
- Author
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Shawn P. Walsh, Jessica Frie, Nardos Teumelsan, Maria L. Garcia, Karen Owens, Sophie Roy, Caryn Hampton, Reynalda K. de Jesus, Birgit T. Priest, Magdalena Alonso-Galicia, Aurash Shahripour, Richard M. Brochu, Juliann Ehrhart, Andrew M. Swensen, Haifeng Tang, Timothy Bailey, Alexander Pasternak, Lee-Yuh Pai, Yuping Zhu, Lihu Yang, Gregory J. Kaczorowski, John P. Felix, Melba Hernandez, Brande Thomas-Fowlkes, and Xiaoyan Zhou
- Subjects
0301 basic medicine ,ERG1 Potassium Channel ,medicine.medical_treatment ,Clinical Biochemistry ,hERG ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,Piperazines ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,0302 clinical medicine ,In vivo ,Heterocyclic Compounds ,Drug Discovery ,medicine ,Potency ,Structure–activity relationship ,Molecular Biology ,biology ,Chemistry ,Organic Chemistry ,Small molecule ,Piperazine ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,ROMK ,Molecular Medicine ,Diuretic - Abstract
Following the discovery of small molecule acyl piperazine ROMK inhibitors and their initial preclinical validation as a novel diuretic agent, our group set out to discover new ROMK inhibitors with reduced risk for QT effects, suitable for further pharmacological experiments in additional species. Several strategies for decreasing hERG affinity while maintaining ROMK inhibition were investigated and are described herein. The most promising candidate, derived from the newly discovered 4-N-heteroaryl acetyl series, improved functional hERG/ROMK ratio by >10× over the previous lead. In vivo evaluation demonstrated comparable diuretic effects in rat with no detectable QT effects at the doses evaluated in an in vivo dog model.
- Published
- 2015
32. 4-Amino-2-alkyl-butyramides as small molecule CCR2 antagonists with favorable pharmacokinetic properties
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Deodialsingh Guiadeen, William H. Parsons, Pasquale P. Vicario, Gregori J. Morriello, Malcolm MacCoss, Margaret A. Cascieri, Shankaran Kothandaraman, Alexander Pasternak, Lihu Yang, and Gabor Butora
- Subjects
CCR2 ,Alkylation ,Receptors, CCR2 ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,chemistry.chemical_compound ,Alicyclic compound ,Cricetinae ,Drug Discovery ,Animals ,Humans ,Receptor ,Molecular Biology ,Cells, Cultured ,Alkyl ,Amination ,chemistry.chemical_classification ,Trifluoromethyl ,Molecular Structure ,Organic Chemistry ,Amides ,Small molecule ,Rats ,chemistry ,Molecular Medicine ,Receptors, Chemokine ,Selectivity ,Lead compound - Abstract
A systematic examination of the central aromatic portion of the lead (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-(4-fluorophenyl)-4-(1′H-spiro[indene-1,4′-piperidin]-1′-yl)butanamide (9) led to the discovery of a novel class of CCR2 receptor antagonists, which carry small alicyclic groups such as cyclopropyl, cylobutyl, or cyclopropylmethyl attached at C2 of the carbon backbone. The most potent compound discovered, namely (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-cyclopropyl-4-[(1R,3′R)-3′-methyl-1′H-spiro[indene-1,4′-piperidin]-1′-yl]butanamide (29), showed very high binding affinity (IC50 = 4 nM, human monocyte) and excellent selectivity toward other related chemokine receptors. The excellent pharmacokinetic profile of this new lead compound allows for extensive in vivo evaluation.
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- 2006
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33. The μ-opioid receptor subtype is required for the anorectic effect of an opioid receptor antagonist
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Andrea Frassetto, Richard Z. Chen, Joseph M. Metzger, Tung M. Fong, Ruey-Ruey C. Huang, Jiaping Zhang, Alexander Pasternak, Sheng-Ping Wang, Julie Z. Lao, and Alison M. Strack
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Male ,medicine.medical_specialty ,medicine.drug_class ,Narcotic Antagonists ,Receptors, Opioid, mu ,Pharmacology ,Eating ,Mice ,chemistry.chemical_compound ,Opioid receptor ,Internal medicine ,Appetite Depressants ,medicine ,Animals ,Humans ,Receptor ,Dose-Response Relationship, Drug ,Chemistry ,Body Weight ,Antagonist ,Enkephalin, Ala(2)-MePhe(4)-Gly(5) ,Rats ,Mice, Inbred C57BL ,DAMGO ,Endocrinology ,Opioid ,Competitive antagonist ,Knockout mouse ,Anorectic ,medicine.drug - Abstract
A diaryl ether derivative, (6-(4-{[(3-methylbutyl)amino]methyl}phenoxy)nicotinamide, was prepared and investigated for its biochemical properties at cloned opioid receptors and its pharmacological effects on animal feeding. The compound displaced [(3)H]DAMGO binding of human mu-opioid receptor, [(3)H]U-69593 of human kappa-opioid receptor, and [(3)H]DPDPE of human delta-opioid receptor with IC(50) values of 0.5+/-0.2 nM, 1.4+/-0.2 nM, and 71+/-15 nM, respectively. The compound also potently inhibited [(3)H]DAMGO binding of cloned mouse and rat mu-opioid receptors (IC(50) approximately 1 nM), and acted as a competitive antagonist in a cAMP functional assay using cultured cells expressing human or mouse mu-opioid receptors. Following a single oral administration in diet-induced obese mice (at 10 or 50 mg/kg) or rats (at 1, 3, or 10 mg/kg), the compound caused a dose-dependent suppression of acute food intake and body weight gain in both species. Importantly, the anorectic efficacy of the compound was mostly diminished in mice deficient in the mu-opioid receptor. Our results suggest an important role for the mu-opioid receptor subtype in animal feeding regulation and support the development of mu-selective antagonists as potential agents for treating human obesity.
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- 2006
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34. Novel, Orally Bioavailable γ-Aminoamide CC Chemokine Receptor 2 (CCR2) Antagonists
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Alexander Pasternak, Pasquale P. Vicario, Margaret A. Cascierri, Sander G. Mills, Julia M. Ayala, Dominick Marino, Malcolm MacCoss, Lihu Yang, and William H. Parsons
- Subjects
CCR2 ,Receptors, CCR5 ,Monocyte chemotaxis ,Receptors, CCR2 ,medicine.drug_class ,Stereochemistry ,Administration, Oral ,Biological Availability ,Carboxamide ,In Vitro Techniques ,Monocytes ,Structure-Activity Relationship ,chemistry.chemical_compound ,Piperidines ,Drug Discovery ,medicine ,Animals ,Structure–activity relationship ,Spiro Compounds ,IC50 ,Chemokine CCL2 ,Trifluoromethyl ,Antagonist ,Stereoisomerism ,Receptors, Neurokinin-1 ,Amides ,Rats ,Chemotaxis, Leukocyte ,Indenes ,chemistry ,CCR5 Receptor Antagonists ,Molecular Medicine ,Receptors, Chemokine ,CC chemokine receptors - Abstract
Through modification of a screening hit we have discovered a structurally distinct new lead, (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-(4-fluorophenyl)-4-(4-phenylpiperidin-1-yl)butanamide (11), which has subsequently served as the departure point for an ongoing program targeting CCR2 antagonists. Optimization of 11 leading to antagonists 26 and 37 is described. Antagonist 26 was shown to have good oral bioavailability in rats. Antagonist 37 had a CCR2 IC50 of 59 nM and excellent potency in a functional assay measuring inhibition of MCP-1 induced monocyte chemotaxis (IC50 of 41 nM).
- Published
- 2006
- Full Text
- View/download PDF
35. Diverse Peptidyl Privileged Structures as Potent Somatostatin Receptor Ligands
- Author
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James M. Schaeffer, Lihu Yang, Ralph T. Mosley, Elizabeth T. Birzin, Alexander Pasternak, Susan P. Rohrer, Yanping Pan, and Arthur A. Patchett
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Biochemistry ,Chemistry ,Somatostatin receptor ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,Somatostatin receptor 2 ,Somatostatin receptor 1 - Published
- 2004
- Full Text
- View/download PDF
36. Design, Synthesis, and Biological Evaluation of Monopyrrolinone-Based HIV-1 Protease Inhibitors
- Author
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Paul A. Sprengeler, Alexander Pasternak, Lawrence C. Kuo, Ralph Hirschmann, Louis-David Cantin, Sanjeev Munshi, William A. Schleif, David B. Olsen, Adam Kenneth Charnley, Wenquin Yao, Amos B. Smith, Lisa Guise-Zawacki, and J. Barbosa
- Subjects
Models, Molecular ,Molecular model ,Stereochemistry ,medicine.medical_treatment ,Biological Availability ,Crystallography, X-Ray ,Dogs ,HIV Protease ,HIV-1 protease ,Indinavir ,Drug Discovery ,Hydrolase ,medicine ,Animals ,Pyrroles ,chemistry.chemical_classification ,Protease ,biology ,HIV Protease Inhibitors ,Protease inhibitor (biology) ,Enzyme ,chemistry ,Enzyme inhibitor ,Drug Design ,Mutation ,biology.protein ,Molecular Medicine ,Carbamates ,Protein Binding ,medicine.drug - Abstract
The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors [(-)-6, (-)-7, (-)-23, (+)-24] based upon the 3,5,5-trisubstituted pyrrolin-4-one scaffold is described. Use of a monopyrrolinone scaffold leads to inhibitors with improved cellular transport properties relative to the earlier inhibitors based on bispyrrolinones and their peptide counterparts. The most potent inhibitor (-)-7 displayed 13% oral bioavailability in dogs. X-ray structure analysis of the monopyrrolinone compounds cocrystallized with the wild-type HIV-1 protease provided valuable information on the interactions between the inhibitors and the HIV-1 enzyme. In each case, the inhibitors assumed similar orientations for the P2'-P1 substituents, along with an unexpected hydrogen bond of the pyrrolinone NH with Asp225. Interactions with the S2 pocket, however, were not optimal, as illustrated by the inclusion of a water molecule in two of the three inhibitor-enzyme complexes. Efforts to increase affinity by displacing the water molecule with second and third generation inhibitors did not prove successful. Lack of success with this venture is a testament to the difficulty of accurately predicting the many variables that influence and build binding affinity. Comparison of the inhibitor positions in three complexes with that of Indinavir revealed displacements of the protease backbones in the enzyme flap region, accompanied by variations in hydrogen bonding to accommodate the monopyrrolinone ring. The binding orientation of the pyrrolinone-based inhibitors may explain their sustained efficacy against mutant strains of the HIV-1 protease enzyme as compared to Indinavir.
- Published
- 2003
- Full Text
- View/download PDF
37. Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes
- Author
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Yang Yu, Gary G. Chicchi, Frederick Wong, Janet S. Kerr, Sharon Tong, Zhe Feng, Guillermo Fernandez, Edward C. Sherer, Kwei-Lan Tsao, Qing Shao, Bei B. Zhang, Yun-Ping Zhou, Pierre Morissette, Shuwen He, Shrenik K. Shah, Vijay Bhasker G. Reddy, Liangqin Guo, Ravi P. Nargund, Margaret Wu, Cai Li, Zhixiong Ye, Alexander Pasternak, George J. Eiermann, Patricia R. Bunting, Hongbo Qi, Michele Pachanski, Stan Mitelman, Maria E. Trujillo, Quang Truong, Maria Madiera, Andrew D. Howard, Donald Nelson, Qingmei Hong, Zhong Lai, Yue Feng, Bindhu V. Karanam, Jian Liu, Koppara Samuel, Wu Du, William K. Hagmann, Tianying Jian, Dorina Trusca, Sylvia Volksdorf, and Peter H. Dobbelaar
- Subjects
business.industry ,Murine model ,Organic Chemistry ,Drug Discovery ,Antagonist ,Qtc interval prolongation ,medicine ,Type 2 diabetes ,Glucose excursion ,Pharmacology ,medicine.disease ,business ,Biochemistry - Abstract
The imidazolyl-tetrahydro-β-carboline class of sstr3 antagonists have demonstrated efficacy in a murine model of glucose excursion and may have potential as a treatment for type 2 diabetes. The first candidate in this class caused unacceptable QTc interval prolongation in oral, telemetrized cardiovascular (CV) dogs. Herein, we describe our efforts to identify an acceptable candidate without CV effects. These efforts resulted in the identification of (1R,3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3H-2-one-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline (17e, MK-1421).
- Published
- 2014
38. Potent, orally bioavailable somatostatin agonists: Good absorption achieved by urea backbone cyclization
- Author
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Kang Cheng, Yanping Pan, Klaus D. Schleim, Su-Er W. Huskey, James M. Schaeffer, Susan P. Rohrer, Lihu Yang, Alexander Pasternak, Ralph T. Mosley, Elizabeth T. Birzin, Dominick Marino, Sanderson Philip E, Tom Jacks, and Arthur A. Patchett
- Subjects
Agonist ,Indoles ,medicine.drug_class ,Stereochemistry ,Clinical Biochemistry ,Administration, Oral ,Biological Availability ,Pharmaceutical Science ,Peptide ,Biochemistry ,Chemical synthesis ,Structure-Activity Relationship ,chemistry.chemical_compound ,Dogs ,Oral administration ,Drug Discovery ,medicine ,Animals ,Urea ,Molecular Biology ,chemistry.chemical_classification ,Dipeptide ,Organic Chemistry ,Bioavailability ,Somatostatin ,chemistry ,Molecular Medicine ,Benzimidazoles - Abstract
Backbone cyclization of urea-based somatostatin agonists resulted in novel, orally bioavailable agonists. Binding assays confirmed that the resulting conformationally constrained cyclic ureas retained the potency of their acyclic counterparts. SAR studies subsequently led to highly potent analogs, selective for receptor subtype 2, and having good oral bioavailability.
- Published
- 1999
- Full Text
- View/download PDF
39. Synthesis and biological activities of potent peptidomimetics selective for somatostatin receptor subtype 2
- Author
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Roger M. Freidinger, Byron H. Arison, Roy G. Smith, Kevin T. Chapman, Kang Cheng, Arthur A. Patchett, Alexander Pasternak, Yanping Pan, Elizabeth T. Birzin, Rupa M. Parmar, Scott C. Berk, Maria A. de Souza Silva, Forrest Foor, Liangqin Guo, James M. Schaeffer, Tsuei-Ju Wu, Sudha W. Mitra, Bridgette S. Butler, Susan P. Rohrer, Edward C. Hayes, Lihu Yang, Ralph T. Mosley, and Dennis J. Underwood
- Subjects
Male ,Agonist ,medicine.medical_specialty ,Indoles ,medicine.drug_class ,CHO Cells ,Biology ,Insulin Antagonists ,Mice ,Cricetinae ,Internal medicine ,medicine ,Somatostatin receptor 3 ,Animals ,Humans ,Insulin ,Somatostatin receptor 2 ,Somatostatin receptor 1 ,Receptors, Somatostatin ,Receptor ,Multidisciplinary ,Somatostatin receptor ,Molecular Mimicry ,Biological Sciences ,Glucagon ,Rats ,Mice, Inbred C57BL ,Endocrinology ,Somatostatin ,Growth Hormone ,Benzimidazoles ,Cyclase activity - Abstract
A series of nonpeptide somatostatin agonists which bind selectively and with high affinity to somatostatin receptor subtype 2 (sst2) have been synthesized. One of these compounds, L-054,522, binds to human sst2 with an apparent dissociation constant of 0.01 nM and at least 3,000-fold selectivity when evaluated against the other somatostatin receptors. L-054,522 is a full agonist based on its inhibition of forskolin-stimulated adenylate cyclase activity in Chinese hamster ovary-K1 cells stably expressing sst2. L-054,522 has a potent inhibitory effect on growth hormone release from rat primary pituitary cells and glucagon release from isolated mouse pancreatic islets. Intravenous infusion of L-054,522 to rats at 50 μg/kg per hr causes a rapid and sustained reduction in growth hormone to basal levels. The high potency and selectivity of L-054,522 for sst2 will make it a useful tool to further characterize the physiological functions of this receptor subtype.
- Published
- 1998
- Full Text
- View/download PDF
40. [Untitled]
- Author
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Masao Sudoh, Ralph Hirschmann, Akihisa Yokoyama, Alexander Pasternak, Amos B. Smith, Giovanni M. Pauletti, William Moser, Ronald T. Borchardt, Paul A. Sprengeler, and Wenqing Yao
- Subjects
Pharmacology ,Protease ,Membrane permeability ,Chemistry ,Stereochemistry ,Peptidomimetic ,medicine.medical_treatment ,Organic Chemistry ,Pharmaceutical Science ,Permeation ,chemistry.chemical_compound ,Intestinal mucosa ,Caco-2 ,Amide ,Biophysics ,medicine ,Molecular Medicine ,Pharmacology (medical) ,Bioisostere ,Biotechnology - Abstract
Purpose. To compare the permeation characteristics of amide bond-containing HIV-1 protease inhibitors and their pyrrolinone-containing counterparts across Caco-2 cell monolayers, a model of the intestinal mucosa.
- Published
- 1998
- Full Text
- View/download PDF
41. Pharmacologic inhibition of the renal outer medullary potassium channel causes diuresis and natriuresis in the absence of kaliuresis
- Author
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Jianying Xiao, John P. Felix, Gregory J. Kaczorowski, Melba Hernandez, Lee-Yuh Pai, Andrew M. Swensen, Magdalena Alonso-Galicia, Alexander Pasternak, Richard M. Brochu, Karen Owens, Kimberly M. Hoagland, Timothy Bailey, Reynalda K. de Jesus, Haifeng Tang, Sophie Roy, Jessica Liu, Birgit T. Priest, Brande Thomas-Fowlkes, Xiaoyan Zhou, and María Luisa Estévez García
- Subjects
Male ,medicine.medical_specialty ,medicine.medical_treatment ,Diuresis ,Natriuresis ,CHO Cells ,Madin Darby Canine Kidney Cells ,Rats, Sprague-Dawley ,Cricetulus ,Dogs ,Internal medicine ,Cricetinae ,medicine ,Loop of Henle ,Potassium Channel Blockers ,Animals ,Humans ,Potassium Channels, Inwardly Rectifying ,Pharmacology ,Dose-Response Relationship, Drug ,Chemistry ,Apical membrane ,Rats ,Endocrinology ,medicine.anatomical_structure ,HEK293 Cells ,Kaliuresis ,Renal physiology ,ROMK ,Molecular Medicine ,Female ,Diuretic - Abstract
The renal outer medullary potassium (ROMK) channel, which is located at the apical membrane of epithelial cells lining the thick ascending loop of Henle and cortical collecting duct, plays an important role in kidney physiology by regulating salt reabsorption. Loss-of-function mutations in the human ROMK channel are associated with antenatal type II Bartter's syndrome, an autosomal recessive life-threatening salt-wasting disorder with mild hypokalemia. Similar observations have been reported from studies with ROMK knockout mice and rats. It is noteworthy that heterozygous carriers of Kir1.1 mutations associated with antenatal Bartter's syndrome have reduced blood pressure and a decreased risk of developing hypertension by age 60. Although selective ROMK inhibitors would be expected to represent a new class of diuretics, this hypothesis has not been pharmacologically tested. Compound A [5-(2-(4-(2-(4-(1H-tetrazol-1-yl)phenyl)acetyl)piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one)], a potent ROMK inhibitor with appropriate selectivity and characteristics for in vivo testing, has been identified. Compound A accesses the channel through the cytoplasmic side and binds to residues lining the pore within the transmembrane region below the selectivity filter. In normotensive rats and dogs, short-term oral administration of compound A caused concentration-dependent diuresis and natriuresis that were comparable to hydrochlorothiazide. Unlike hydrochlorothiazide, however, compound A did not cause any significant urinary potassium losses or changes in plasma electrolyte levels. These data indicate that pharmacologic inhibition of ROMK has the potential for affording diuretic/natriuretic efficacy similar to that of clinically used diuretics but without the dose-limiting hypokalemia associated with the use of loop and thiazide-like diuretics.
- Published
- 2013
42. Pyrrolinone-Based HIV Protease Inhibitors. Design, Synthesis, and Antiviral Activity: Evidence for Improved Transport
- Author
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Paul A. Sprengeler, Akihisa Yokoyama, Alexander Pasternak, Paul L. Darke, Emilio A. Emini, William A. Schleif, Ralph Hirschmann, Mark C. Guzman, and Amos B. Smith
- Subjects
Colloid and Surface Chemistry ,Design synthesis ,Chemistry ,HIV Protease Inhibitor ,General Chemistry ,Biochemistry ,Virology ,Catalysis - Published
- 1995
- Full Text
- View/download PDF
43. Viscosity evaluation of the mixture of coal tars from collection main and primary cooler on the base of rheometer measurements and empirical formulas
- Author
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Alexander Pasternak, Anna Smirnova, and Leonid Bannikov
- Subjects
Base (chemistry) ,viruses ,Rheometer ,Energy Engineering and Power Technology ,Thermodynamics ,Activation energy ,complex mixtures ,Industrial and Manufacturing Engineering ,Viscosity ,Management of Technology and Innovation ,otorhinolaryngologic diseases ,medicine ,Coal ,Electrical and Electronic Engineering ,Coal tar ,chemistry.chemical_classification ,Petroleum engineering ,business.industry ,Chemistry ,Applied Mathematics ,Mechanical Engineering ,technology, industry, and agriculture ,Tar ,Computer Science Applications ,Control and Systems Engineering ,Empirical relationship ,business ,medicine.drug - Abstract
Viscosity of heavy and light coal tars from the coking process of coal blends with a decreasing portion of Ukrainian coal was measured. In addition, measurement of viscosity of mixtures of coal tar was carried out. Concentration of mixture met the standards of the regulations of the washing liquids for gas space of primary cooler. The temperature dependence of the viscosity of the tar mixture was evaluated according to some empirical equations. In particular, the equations have been used considering deviations from the ideal state. The viscosity of the individual samples of heavy and light tars was not appropriately investigated. This also applies to the temperature dependence. This is common practice for coal tar viscosity measurements in Engler units. Also, there are no empirical relationships; we cannot predict the viscosity of the tar when mixed, as we do for the petroleum oil matter. Anomalous decline in viscosity with the addition of 5–20 % light tar that corresponded to the minimum activation energy of viscous flow was revealed experimentally.
- Published
- 2016
- Full Text
- View/download PDF
44. Discovery of Selective Small Molecule ROMK Inhibitors as Potential New Mechanism Diuretics
- Author
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Nardos Teumelsan, Alexander Pasternak, John P. Felix, Yan Yan, Reynalda K. de Jesus, Brande Thomas-Fowlkes, Maria L. Garcia, Gregory J. Kaczorowski, Lihu Yang, Haifeng Tang, Sophie Roy, Richard M. Brochu, Jessica Liu, Sookhee Ha, Shawn P. Walsh, Karen Owens, Birgit T. Priest, Magdalena Alonso-Galicia, Aurash Shahripour, Martin Köhler, Sander G. Mills, Yuping Zhu, and Timothy Bailey
- Subjects
biology ,Inward-rectifier potassium ion channel ,business.industry ,Organic Chemistry ,hERG ,Drug target ,RENAL OUTER-MEDULLARY POTASSIUM CHANNEL ,Pharmacology ,Biochemistry ,Small molecule ,Potassium channel ,In vivo ,Drug Discovery ,ROMK ,biology.protein ,Medicine ,business - Abstract
The renal outer medullary potassium channel (ROMK or Kir1.1) is a putative drug target for a novel class of diuretics that could be used for the treatment of hypertension and edematous states such as heart failure. An internal high-throughput screening campaign identified 1,4-bis(4-nitrophenethyl)piperazine (5) as a potent ROMK inhibitor. It is worth noting that this compound was identified as a minor impurity in a screening hit that was responsible for all of the initially observed ROMK activity. Structure–activity studies resulted in analogues with improved rat pharmacokinetic properties and selectivity over the hERG channel, providing tool compounds that can be used for in vivo pharmacological assessment. The featured ROMK inhibitors were also selective against other members of the inward rectifier family of potassium channels.
- Published
- 2012
45. Enantioretentive alkylation of oxazolidinone aluminum enolates with epoxides: Preparation of uncoded homoserine analogs
- Author
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Ralph Hirschmann, Amos B. Smith, Alexander Pasternak, and Akihisa Yokoyama
- Subjects
chemistry.chemical_compound ,Chemistry ,Organic Chemistry ,Drug Discovery ,medicine ,Homoserine ,Enantioselective synthesis ,Organic chemistry ,Alkylation ,Biochemistry ,Chloride ,medicine.drug ,Adduct - Abstract
The alkylation of Karady/Seebach oxazolidinone enolates with epoxides, promoted by 2.1 equivalents of diethylaluminum chloride, furnishes ring-opened adducts in moderate-to-good yields with high diastereoselectivity. The method provides an effective approach to uncoded homoserine analogs and expands the utility of readily available oxazolidinones in asymmetric synthesis.
- Published
- 1994
- Full Text
- View/download PDF
46. Stimulation of Glucose-Dependent Insulin Secretion by a Potent, Selective sst3 Antagonist
- Author
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Peter H. Dobbelaar, Margaret Wu, Cai Li, Gary G. Chicchi, Lihu Yang, Dorina Trusca, Yue Feng, Scott A. Bradley, Kwei-Lan Tsao, Reynalda K. de Jesus, Ravi P. Nargund, Bei B. Zhang, Zhixiong Ye, Andrew D. Howard, Qing Shao, Yun-Ping Zhou, Shuwen He, Zhe Feng, Sander G. Mills, Alexander Pasternak, and George J. Eiermann
- Subjects
medicine.medical_specialty ,business.industry ,Organic Chemistry ,Antagonist ,Type 2 Diabetes Mellitus ,Stimulation ,Type 2 diabetes ,medicine.disease ,Biochemistry ,Somatostatin ,Endocrinology ,Internal medicine ,Drug Discovery ,Knockout mouse ,medicine ,Antagonism ,business ,Receptor - Abstract
This letter provides the first pharmacological proof of principle that the sst3 receptor mediates glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. To enable these studies, we identified the selective sst3 antagonist (1R,3R)-3-(5-phenyl-1H-imidazol-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-β-carboline (5a), with improved ion channel selectivity and mouse pharmacokinetic properties as compared to previously described tetrahydro-β-carboline imidazole sst3 antagonists. We demonstrated that compound 5a enhances GSIS in pancreatic β-cells and blocks glucose excursion induced by dextrose challenge in ipGTT and OGTT models in mice. Finally, we provided strong evidence that these effects are mechanism-based in an ipGTT study, showing reduction of glucose excursion in wild-type but not sst3 knockout mice. Thus, we have shown that antagonism of sst3 represents a new mechanism with potential in treating type 2 diabetes mellitus.
- Published
- 2011
47. ChemInform Abstract: Enantioretentive Alkylation of Oxazolidinone Aluminum Enolates with Epoxides: Preparation of Uncoded Homoserine Analogues
- Author
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Alexander Pasternak, Akihisa Yokoyama, Ralph Hirschmann, and Amos B. Smith
- Subjects
chemistry.chemical_compound ,chemistry ,Homoserine ,Organic chemistry ,General Medicine ,Alkylation - Published
- 2010
- Full Text
- View/download PDF
48. ChemInform Abstract: Pyrrolinone-Based HIV Protease Inhibitors. Design, Synthesis, and Antiviral Activity: Evidence for Improved Transport
- Author
-
Emilio A. Emini, Alexander Pasternak, William A. Schleif, Ralph Hirschmann, Paul A. Sprengeler, Akihisa Yokoyama, Mark C. Guzman, Amos B. Smith, and Paul L. Darke
- Subjects
Design synthesis ,Biochemistry ,Chemistry ,medicine.drug_class ,Antibiotics ,medicine ,HIV Protease Inhibitor ,General Medicine ,Pyrrole derivatives - Published
- 2010
- Full Text
- View/download PDF
49. ChemInform Abstract: Potent, Orally Bioavailable Somatostatin Agonists: Good Absorption Achieved by Urea Backbone Cyclization
- Author
-
Alexander Pasternak and et al. et al.
- Subjects
chemistry.chemical_compound ,Somatostatin ,Chemistry ,Urea ,General Medicine ,Absorption (electromagnetic radiation) ,Bioavailability ,Nuclear chemistry - Published
- 2010
- Full Text
- View/download PDF
50. Discovery of a Potent and Orally Bioavailable CCR2 and CCR5 Dual Antagonist
- Author
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Julia M. Ayala, Lihu Yang, Julie A. DeMartino, Pasquale P. Vicario, Jerry Di Salvo, Stephen D. Goble, Mary Struthers, Alexander Pasternak, Ruth Kilburn, Sander G. Mills, and Thomas Wisniewski
- Subjects
CCR2 ,business.industry ,animal diseases ,Organic Chemistry ,Antagonist ,hemic and immune systems ,Pharmacology ,Biochemistry ,Bioavailability ,parasitic diseases ,Drug Discovery ,Medicine ,Potency ,business ,CC chemokine receptors - Abstract
This report describes the discovery of a potent, orally bioavailable CC chemokine receptor 2 (CCR2) antagonist which, while optimized for CCR2 potency, also had potent CC chemokine receptor 5 (CCR5) activity.
- Published
- 2009
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