184 results on '"John E. Macor"'
Search Results
2. Site-Selective C–H Functionalization of N-Aryl and N-Heteroaryl Piperidines, Morpholines, and Piperazines Controlled by a Chiral Dirhodium Tetracarboxylate Catalyst
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Korkit Korvorapun, Yannick T. Boni, Thomas C. Maier, Armin Bauer, Thomas Licher, John E. Macor, Volker Derdau, and Huw M. L. Davies
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General Chemistry ,Catalysis - Published
- 2023
3. Discovery of 2-(Anilino)pyrimidine-4-carboxamides as Highly Potent, Selective, and Orally Active Glycogen Synthase Kinase-3 (GSK-3) Inhibitors
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Richard A. Hartz, Vijay T. Ahuja, Guanglin Luo, Ling Chen, Prasanna Sivaprakasam, Hong Xiao, Carol M. Krause, Wendy J. Clarke, Songmei Xu, John S. Tokarski, Kevin Kish, Hal Lewis, Nicolas Szapiel, Ramu Ravirala, Sayali Mutalik, Deepa Nakmode, Devang Shah, Catherine R. Burton, John E. Macor, and Gene M. Dubowchik
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Drug Discovery ,Molecular Medicine - Published
- 2023
4. Structure-Activity Relationship (SAR) Studies on Substituted 2-(Pyridin-2-ylamino)-N-(pyridin-3-yl)isonicotinamide as Highly Potent, Selective and Brain Penetrant Glycogen Synthase Kinase-3 (GSK-3) Inhibitors
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Guanglin Luo, Ling Chen, Swanee Jacutin-Porte, Catherine R. Burton, Hong Xiao, Prasanna Sivaprakasam, Carol M. Krause, Yang Cao, Nengyin Liu, Michelle Nophsker, Kimberly Snow, Wendy J. Clarke, Kevin Kish, Hal Lewis, John E. Macor, and Gene M. Dubowchik
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- 2023
5. Discovery and Optimization of Biaryl Alkyl Ethers as a Novel Class of Highly Selective, CNS-Penetrable, and Orally Active Adaptor Protein-2-Associated Kinase 1 (AAK1) Inhibitors for the Potential Treatment of Neuropathic Pain
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Guanglin Luo, Ling Chen, Walter A. Kostich, Brian Hamman, Jason Allen, Amy Easton, Clotilde Bourin, Michael Gulianello, Jonathan Lippy, Susheel Nara, Sreenivasulu Naidu Pattipati, Kumaran Dandapani, Manoj Dokania, Pradeep Vattikundala, Vivek Sharma, Saravanan Elavazhagan, Manoj Kumar Verma, Manish Lal Das, Santosh Wagh, Anand Balakrishnan, Benjamin M. Johnson, Kenneth S. Santone, George Thalody, Rex Denton, Hariharan Saminathan, Vinay K. Holenarsipur, Anoop Kumar, Abhijith Rao, Siva Prasad Putlur, Sarat Kumar Sarvasiddhi, Ganesh Shankar, Justin V. Louis, Manjunath Ramarao, Charles M. Conway, Yu-Wen Li, Rick Pieschl, Yuan Tian, Yang Hong, Linda Bristow, Charles F. Albright, Joanne J. Bronson, John E. Macor, and Carolyn D. Dzierba
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Mice ,Structure-Activity Relationship ,Spinal Cord ,Anesthetics, General ,Drug Discovery ,Animals ,Neuralgia ,Molecular Medicine ,Protein Kinase Inhibitors ,Ethers ,Rats - Abstract
Recent mouse knockout studies identified adapter protein-2-associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. BMS-986176/LX-9211 (
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- 2022
6. Discovery of (S)-1-((2′,6-Bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211): A Highly Selective, CNS Penetrable, and Orally Active Adaptor Protein-2 Associated Kinase 1 Inhibitor in Clinical Trials for the Treatment of Neuropathic Pain
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Guanglin Luo, Ling Chen, Walter A. Kostich, Brian Hamman, Jason Allen, Amy Easton, Clotilde Bourin, Michael Gulianello, Jonathan Lippy, Susheel Nara, Tarun Kumar Maishal, Kamalraj Thiyagarajan, Prasadrao Jalagam, Sreenivasulu Naidu Pattipati, Kumaran Dandapani, Manoj Dokania, Pradeep Vattikundala, Vivek Sharma, Saravanan Elavazhagan, Manoj Kumar Verma, Manish Lal Das, Santosh Wagh, Anand Balakrishnan, Benjamin M. Johnson, Kenneth S. Santone, George Thalody, Rex Denton, Hariharan Saminathan, Vinay K. Holenarsipur, Anoop Kumar, Abhijith Rao, Siva Prasad Putlur, Sarat Kumar Sarvasiddhi, Ganesh Shankar, Justin V. Louis, Manjunath Ramarao, Charles M. Conway, Yu-Wen Li, Rick Pieschl, Yuan Tian, Yang Hong, Jonathan Ditta, Arvind Mathur, Jianqing Li, Daniel Smith, Joseph Pawluczyk, Dawn Sun, Shiuhang Yip, Dauh-Rurng Wu, Muthalagu Vetrichelvan, Anuradha Gupta, Alan Wilson, Suma Gopinathan, Suman Wason, Linda Bristow, Charles F. Albright, Joanne J. Bronson, John E. Macor, and Carolyn D. Dzierba
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Drug Discovery ,Molecular Medicine - Published
- 2022
7. Bicyclic Heterocyclic Replacement of an Aryl Amide Leading to Potent and Kinase-Selective Adaptor Protein 2-Associated Kinase 1 Inhibitors
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Richard A. Hartz, Vijay T. Ahuja, Susheel J. Nara, C. M. Vijaya Kumar, Raju K. V. L. P. Manepalli, Sarat Kumar Sarvasiddhi, Swarnamba Honkhambe, Vidya Patankar, Bireshwar Dasgupta, Ramkumar Rajamani, Jodi K. Muckelbauer, Daniel M. Camac, Kaushik Ghosh, Matthew Pokross, Susan E. Kiefer, Jeffrey M. Brown, Lisa Hunihan, Michael Gulianello, Martin Lewis, Jonathan S. Lippy, Neha Surti, Brian D. Hamman, Jason Allen, Walter A. Kostich, Joanne J. Bronson, John E. Macor, and Carolyn D. Dzierba
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Structure-Activity Relationship ,Drug Discovery ,Quinazolines ,Quinolines ,Animals ,Neuralgia ,Molecular Medicine ,Amides ,Protein Kinase Inhibitors - Abstract
Adaptor protein 2-associated kinase 1 (AAK1) is a serine/threonine kinase that was identified as a therapeutic target for the potential treatment of neuropathic pain. Inhibition of AAK1 in the central nervous system, particularly within the spinal cord, was found to be the relevant site for achieving an antinociceptive effect. We previously reported that compound
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- 2022
8. Development of a Rapid Scale-Up Synthesis of (S)-N-(8-((2-Amino-2,4-dimethylpentyl)oxy)-5H-chromeno[3,4-c]pyridin-2-yl)acetamide, a Potent Adaptor-Associated Kinase 1 Inhibitor
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Jianqing Li, Daniel Smith, Joseph Pawluczyk, Subramaniam Krishnananthan, Bei Wang, Xiaoping Hou, Rulin Zhao, James Kempson, Dawn Sun, Shiuhang Yip, Dauh-Rurng Wu, Nageswararao Maddala, Muthalagu Vetrichelvan, Anuradha Gupta, John E. Macor, Carolyn D. Dzierba, and Arvind Mathur
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Organic Chemistry ,Physical and Theoretical Chemistry - Published
- 2022
9. Structure–activity relationship (SAR) studies on substituted N-(pyridin-3-yl)-2-amino-isonicotinamides as highly potent and selective glycogen synthase kinase-3 (GSK-3) inhibitors
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Guanglin Luo, Ling Chen, Swanee Jacutin-Porte, Ying Han, Catherine R. Burton, Hong Xiao, Carol M. Krause, Yang Cao, Nengyin Liu, Kevin Kish, Hal A. Lewis, John E. Macor, and Gene M. Dubowchik
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Organic Chemistry ,Clinical Biochemistry ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,Molecular Biology ,Biochemistry - Published
- 2023
10. Discovery of BMS-986202: A Clinical Tyk2 Inhibitor that Binds to Tyk2 JH2
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Jianqing Li, Daniel Smith, John S. Tokarski, Lihong Cheng, John E. Macor, Javed Khan, Adriana Zupa-Fernandez, Anil Thankappan, Chunjian Liu, Charu Chaudhry, David S. Weinstein, Percy H. Carter, Kathleen M. Gillooly, Kim W. McIntyre, Yifan Zhang, Anjaneya Chimalakonda, Joann Strnad, James Lin, James R. Burke, David J. Shuster, Manoj Chiney, Paul A. Elzinga, Max Ruzanov, Louis J. Lombardo, and Charles M. Langevine
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Cyclopropanes ,TYK2 Kinase ,Chemistry ,Hydrogen bond ,Drug discovery ,Ligand ,Stereochemistry ,Plasma protein binding ,Crystallography, X-Ray ,Catalysis ,Pyridazine ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Amide ,Drug Discovery ,Animals ,Humans ,Psoriasis ,Molecular Medicine ,Structure–activity relationship ,Moiety ,Oxazoles ,Protein Kinase Inhibitors ,Protein Binding - Abstract
A search for structurally diversified Tyk2 JH2 ligands from 6 (BMS-986165), a pyridazine carboxamide-derived Tyk2 JH2 ligand as a clinical Tyk2 inhibitor currently in late development for the treatment of psoriasis, began with a survey of six-membered heteroaryl groups in place of the N-methyl triazolyl moiety in 6. The X-ray co-crystal structure of an early lead (12) revealed a potential new binding pocket. Exploration of the new pocket resulted in two frontrunners for a clinical candidate. The potential hydrogen bonding interaction with Thr599 in the pocket was achieved with a tertiary amide moiety, confirmed by the X-ray co-crystal structure of 29. When the diversity search was extended to nicotinamides, a single fluorine atom addition was found to significantly enhance the permeability, which directly led to the discovery of 7 (BMS-986202) as a clinical Tyk2 inhibitor that binds to Tyk2 JH2. The preclinical studies of 7, including efficacy studies in mouse models of IL-23-driven acanthosis, anti-CD40-induced colitis, and spontaneous lupus, will also be presented.
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- 2020
11. Biologic-like In Vivo Efficacy with Small Molecule Inhibitors of TNFα Identified Using Scaffold Hopping and Structure-Based Drug Design Approaches
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Mian Gao, David J. Shuster, Hai-Yun Xiao, Christine B. Goldstine, Jing Chen, Zhonghui Lu, Victor R. Guarino, Khehyong Ngu, Lisa M. Kopcho, Deepa Calambur, Kurt R. Gregor, Andrew J. Tebben, Jingwu Duan, Luisa Salter-Cid, Hao Lu, Joseph A. Tino, Ning Li, John Hynes, James R. Burke, Joseph Yanchunas, John E. Macor, Steven Sheriff, Dauh-Rurng Wu, Bin Jiang, Patrick J. Shaw, ChiehYing Y. Chang, Jenny Xie, Vojkan Susulic, and T. G. Murali Dhar
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Arthritis ,Trimer ,Proof of Concept Study ,01 natural sciences ,Arthritis, Rheumatoid ,Structure-Activity Relationship ,03 medical and health sciences ,Pharmacokinetics ,In vivo ,Drug Discovery ,medicine ,Animals ,Humans ,Potency ,Structure–activity relationship ,Naphthyridines ,030304 developmental biology ,0303 health sciences ,Molecular Structure ,Tumor Necrosis Factor-alpha ,Chemistry ,medicine.disease ,Arthritis, Experimental ,Small molecule ,0104 chemical sciences ,Mice, Inbred C57BL ,010404 medicinal & biomolecular chemistry ,Drug Design ,Microsomes, Liver ,Quinolines ,Biophysics ,Molecular Medicine ,Female ,Tumor necrosis factor alpha - Abstract
Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFα). Structure-activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFα trimer upon binding, leading to aberrant signaling when the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic-pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a collagen antibody-induced arthritis model, where it showed biologic-like in vivo efficacy, will be discussed.
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- 2020
12. Novel Tricyclic Pyroglutamide Derivatives as Potent RORγt Inverse Agonists Identified using a Virtual Screening Approach
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Tara Sherry, John E. Macor, Jinhong Wang, Georgia Cornelius, Shiuhang Yip, Luisa Salter-Cid, Qingjie Liu, Purnima Khandelwal, Carolyn A. Weigelt, Max Ruzanov, John S. Sack, Kevin Stefanski, Jenny Xie, T. G. Murali Dhar, Sha Li, Melissa Yarde, Joseph A. Tino, Qihong Zhao, Dauh-Rurng Wu, Mary T. Obermeier, David J. Shuster, Aberra Fura, Douglas G. Batt, and Rex Denton
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chemistry.chemical_classification ,Virtual screening ,010405 organic chemistry ,Stereochemistry ,Organic Chemistry ,Prodrug ,Cyclohexanecarboxylic acid ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,chemistry ,RAR-related orphan receptor gamma ,Drug Discovery ,Moiety ,Inverse agonist ,Solubility ,Tricyclic - Abstract
[Image: see text] Employing a virtual screening approach, we identified the pyroglutamide moiety as a nonacid replacement for the cyclohexanecarboxylic acid group which, when coupled to our previously reported conformationally locked tricyclic core, provided potent and selective RORγt inverse agonists. Structure–activity relationship optimization of the pyroglutamide moiety led to the identification of compound 18 as a potent and selective RORγt inverse agonist, albeit with poor aqueous solubility. We took advantage of the tertiary carbinol group in 18 to synthesize a phosphate prodrug, which provided good solubility, excellent exposures in mouse PK studies, and significant efficacy in a mouse model of psoriasis.
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- 2020
13. Discovery of (
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Guanglin, Luo, Ling, Chen, Walter A, Kostich, Brian, Hamman, Jason, Allen, Amy, Easton, Clotilde, Bourin, Michael, Gulianello, Jonathan, Lippy, Susheel, Nara, Tarun Kumar, Maishal, Kamalraj, Thiyagarajan, Prasadrao, Jalagam, Sreenivasulu Naidu, Pattipati, Kumaran, Dandapani, Manoj, Dokania, Pradeep, Vattikundala, Vivek, Sharma, Saravanan, Elavazhagan, Manoj Kumar, Verma, Manish Lal, Das, Santosh, Wagh, Anand, Balakrishnan, Benjamin M, Johnson, Kenneth S, Santone, George, Thalody, Rex, Denton, Hariharan, Saminathan, Vinay K, Holenarsipur, Anoop, Kumar, Abhijith, Rao, Siva Prasad, Putlur, Sarat Kumar, Sarvasiddhi, Ganesh, Shankar, Justin V, Louis, Manjunath, Ramarao, Charles M, Conway, Yu-Wen, Li, Rick, Pieschl, Yuan, Tian, Yang, Hong, Jonathan, Ditta, Arvind, Mathur, Jianqing, Li, Daniel, Smith, Joseph, Pawluczyk, Dawn, Sun, Shiuhang, Yip, Dauh-Rurng, Wu, Muthalagu, Vetrichelvan, Anuradha, Gupta, Alan, Wilson, Suma, Gopinathan, Suman, Wason, Linda, Bristow, Charles F, Albright, Joanne J, Bronson, John E, Macor, and Carolyn D, Dzierba
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Mice ,Spinal Cord ,Animals ,Brain ,Neuralgia ,Amines ,Protein Kinase Inhibitors ,Rats - Abstract
Recent mouse knockout studies identified adapter protein-2 associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. Potent small-molecule inhibitors of AAK1 have been identified and show efficacy in various rodent pain models. (
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- 2022
14. Rationally Designed, Conformationally Constrained Inverse Agonists of RORγt—Identification of a Potent, Selective Series with Biologic-Like in Vivo Efficacy
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Carolyn A. Weigelt, Sha Li, David Marcoux, Georgia Cornelius, Qihong Zhao, Mary Ellen Cvijic, John E. Macor, Jingwu Duan, Melissa Yarde, Muthalagu Vetrichelvan, David J. Shuster, Qingjie Liu, Richard Rampulla, Kim W. McIntyre, Mary T. Obermeier, Shiuhang Yip, Purnima Khandelwal, Sureshbabu Vishwakrishnan, Anuradha Gupta, Virna Borowski, Peng Li, Kevin Stefanski, Sridharan Ramlingam, Myra Beaudoin-Bertrand, Nageswara Maddala, Sridhar Vanteru, Percy H. Carter, Arvind Mathur, Aberra Fura, Max Ruzanov, John Hynes, Dauh-Rurng Wu, Jinhong Wang, Luisa Salter-Cid, John S. Sack, Cornelius Lyndon A M, Anurag S. Srivastava, Robert J. Cherney, Kumaravel Selvakumar, Mushkin Basha, Arun Kumar Gupta, Douglas G. Batt, Rex Denton, Sukhen Karmakar, Qing Shi, Ananta Karmakar, Naveen Manjunath, Javed Khan, Jenny Xie, Joseph A. Tino, and T. G. Murali Dhar
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Models, Molecular ,Pyrrolidines ,Drug Inverse Agonism ,Protein Conformation ,Pharmacology ,01 natural sciences ,Jurkat Cells ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,Psoriatic arthritis ,RAR-related orphan receptor gamma ,In vivo ,Drug Discovery ,medicine ,Animals ,Humans ,Inverse agonist ,Structure–activity relationship ,Tissue Distribution ,030304 developmental biology ,0303 health sciences ,Chemistry ,Nuclear Receptor Subfamily 1, Group F, Member 3 ,medicine.disease ,In vitro ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Nuclear receptor ,Drug Design ,Molecular Medicine - Abstract
RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORγt has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORγt inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORγt inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule 32 with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.
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- 2019
15. What I Did on My Summer Vacation and Molecules That Broke My Heart: Insights from a 35-Year Adventure In Drug Discovery
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John E. Macor
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- 2021
16. Identification and characterization of a MAPT-targeting locked nucleic acid antisense oligonucleotide therapeutic for tauopathies
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Amy Easton, Marianne L. Jensen, Congwei Wang, Peter H. Hagedorn, Yuwen Li, Michael Weed, Jere E. Meredith, Valerie Guss, Kelli Jones, Martin Gill, Carol Krause, Jeffrey M. Brown, Lisa Hunihan, Joanne Natale, Alda Fernandes, Yifeng Lu, Joe Polino, Mark Bookbinder, Greg Cadelina, Yulia Benitex, Ramola Sane, John Morrison, Dieter Drexler, Stephen E. Mercer, Charlotte Bon, Nikhil J. Pandya, Ravi Jagasia, Tai-Hsien Ou Yang, Tania Distler, Fiona Grüninger, Michael Meldgaard, Marco Terrigno, John E. Macor, Charles F. Albright, James Loy, Anja M. Hoeg, Richard E. Olson, and Angela M. Cacace
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Drug Discovery ,Molecular Medicine - Abstract
Tau is a microtubule-associated protein (
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- 2021
17. Discovery, Structure-Activity Relationships, and In Vivo Evaluation of Novel Aryl Amides as Brain Penetrant Adaptor Protein 2-Associated Kinase 1 (AAK1) Inhibitors for the Treatment of Neuropathic Pain
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Jodi K. Muckelbauer, Ramkumar Rajamani, Jeffrey M. Brown, C M Vijaya Kumar, Kumaran Dandapani, Jonathan Lippy, Saravanan Elavazhagan, Vijay T. Ahuja, John E. Macor, Carolyn Diane Dzierba, Brian D. Hamman, Walter Kostich, Michael Gulianello, Manoj Dokania, Susan E. Kiefer, Susheel J. Nara, Joanne J. Bronson, Amy Easton, Richard A. Hartz, Linda J. Bristow, Martin A. Lewis, Jason Allen, Sreenivasulu N Pattipati, Neha Surti, Lisa Hunihan, and Daniel M. Camac
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Male ,Phenotypic screening ,Pharmacology ,Protein Serine-Threonine Kinases ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,In vivo ,Drug Discovery ,medicine ,Animals ,Humans ,Dose-Response Relationship, Drug ,Molecular Structure ,Kinase ,Chemistry ,Anti-Inflammatory Agents, Non-Steroidal ,Chronic pain ,AAK1 ,Signal transducing adaptor protein ,Brain ,medicine.disease ,Amides ,Mice, Inbred C57BL ,HEK293 Cells ,Neuropathic pain ,Microsomes, Liver ,Molecular Medicine ,Neuralgia ,Caco-2 Cells ,Penetrant (biochemical) ,Protein Kinases - Abstract
Effective treatment of chronic pain, in particular neuropathic pain, without the side effects that often accompany currently available treatment options is an area of significant unmet medical need. A phenotypic screen of mouse gene knockouts led to the discovery that adaptor protein 2-associated kinase 1 (AAK1) is a potential therapeutic target for neuropathic pain. The synthesis and optimization of structure-activity relationships of a series of aryl amide-based AAK1 inhibitors led to the identification of 59, a brain penetrant, AAK1-selective inhibitor that proved to be a valuable tool compound. Compound 59 was evaluated in mice for the inhibition of μ2 phosphorylation. Studies conducted with 59 in pain models demonstrated that this compound was efficacious in the phase II formalin model for persistent pain and the chronic-constriction-injury-induced model for neuropathic pain in rats. These results suggest that AAK1 inhibition is a promising approach for the treatment of neuropathic pain.
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- 2021
18. Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage
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Charu Chaudhry, Ping Zhang, Kyoung S. Kim, William J. Pitts, Cornelius Lyndon A M, Lynn M. Abell, Hart Amy C, Kevin O’Malley, Junqing Guo, Brian Carpenter, Hao Lu, Ramesh Padmanabha, Patrick J. Shaw, Mertzman Michael E, Kevin Kish, Andrew E Douglas, Matthew Pokross, John E. Macor, Deepa Calambur, and Carolyn A. Weigelt
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010405 organic chemistry ,Kinase ,Chemistry ,Necroptosis ,Organic Chemistry ,Computational biology ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Drug Discovery ,Transferase ,Identification (biology) ,Signal transduction - Abstract
[Image: see text] Necroptosis has been implicated in a variety of disease states, and RIPK3 is one of the kinases identified to play a critical role in this signaling pathway. In an effort to identify RIPK3 kinase inhibitors with a novel profile, mechanistic studies were incorporated at the hit triage stage. Utilization of these assays enabled identification of a Type II DFG-out inhibitor for RIPK3, which was confirmed by protein crystallography. Structure-based drug design on the inhibitors targeting this previously unreported conformation enabled an enhancement in selectivity against key off-target kinases.
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- 2019
19. The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu4 PAM development candidate
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Corey R. Hopkins, Anna L. Blobaum, Joshua M. Wieting, Ryan Westphal, Rory A. Capstick, Alison R. Gregro, Julie E. Engers, Aspen Chun, P. Jeffrey Conn, Jason M. Guernon, Carrie K. Jones, Alice L. Rodriguez, Darren W. Engers, Joseph D. Panarese, Craig W. Lindsley, Wu Yong Jin, Joanne J. Bronson, John E. Macor, Andrew S. Felts, Kyle A. Emmitte, Colleen M. Niswender, Aaron M. Bender, and Matthew Soars
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Allosteric modulator ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Computational biology ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Cns penetration ,010404 medicinal & biomolecular chemistry ,Metabotropic glutamate receptor ,Drug Discovery ,Molecular Medicine ,skin and connective tissue diseases ,Molecular Biology - Abstract
This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu4 positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration).
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- 2019
20. Discovery of VU2957 (Valiglurax): An mGlu4 Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson’s Disease
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Michael J. Kates, Arlindo L. Castelhano, Carrie K. Jones, Colleen M. Niswender, Andrew S. Felts, Anna L. Blobaum, Matthew T. Loch, Kyle A. Emmitte, Aspen Chun, John E. Macor, Joanne J. Bronson, Darren W. Engers, Alice L. Rodriguez, Julie L. Engers, Joseph D. Panarese, Craig W. Lindsley, Michael A. Nader, Wu Yong Jin, P. Jeffrey Conn, and Corey R. Hopkins
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Allosteric modulator ,Parkinson's disease ,010405 organic chemistry ,business.industry ,Organic Chemistry ,Pharmacology ,medicine.disease ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Toxicology studies ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,chemistry ,In vivo ,Drug Discovery ,medicine ,business ,Penetrant (biochemical) - Abstract
[Image: see text] Herein, we report the discovery of a novel potent, selective, CNS penetrant, and orally bioavailable mGlu(4) PAM, VU0652957 (VU2957, Valiglurax). VU2957 possessed attractive in vitro and in vivo pharmacological and DMPK properties across species. To advance toward the clinic, a spray-dried dispersion (SDD) formulation of VU2957 was developed to support IND-enabling toxicology studies. Based on its overall profile, VU2957 was evaluated as a preclinical development candidate for the treatment of Parkinson’s disease.
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- 2018
21. Azepino-indazoles as calcitonin gene-related peptide (CGRP) receptor antagonists
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Sokhom S. Pin, Deborah A. Cook, John E. Macor, Laura J. Signor, Carl Davis, Valerie J. Whiterock, Gene M. Dubowchik, Richard Schartman, Ping Chen, Chaturvedula Prasad, Kimberly A. Widmann, George Thalody, Walter Kostich, Robert Macci, John J. Herbst, Stephen E. Mercer, Charles M. Conway, and Cen Xu
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Indazoles ,Clinical Biochemistry ,Pharmaceutical Science ,Peptide ,Calcitonin gene-related peptide ,Pharmacology ,01 natural sciences ,Biochemistry ,Structure-Activity Relationship ,In vivo ,Calcitonin Gene-Related Peptide Receptor Antagonists ,Drug Discovery ,Humans ,Receptor ,Molecular Biology ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Antagonist ,Azepines ,0104 chemical sciences ,Bioavailability ,010404 medicinal & biomolecular chemistry ,Calcitonin ,Molecular Medicine ,Nasal administration ,Receptors, Calcitonin Gene-Related Peptide - Abstract
Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown clinically to be effective treatments for migraine. Zavegepant (BHV-3500, BMS-742413) is a high affinity antagonist of the CGRP receptor (hCGRP Ki = 0.023 nM) that has demonstrated efficacy in the acute treatment of migraine with intranasal delivery in a Phase 2/3 trial, despite showing low oral bioavailability in rats (FPO = 1.7%). Using zavegepant as a template, we sought to improve oral bioavailability through a series of azepinones which were designed in an attempt to reduce the number of rotatable bonds. These efforts led to the discovery of compound 21 which was able to mostly maintain high affinity binding (hCGRP Ki = 0.100 nM) and in vivo efficacy in the marmoset facial blood flow assay, while greatly improving oral bioavailability (rat FPO = 17%).
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- 2020
22. Discovery of BMS-986251: A Clinically Viable, Potent, and Selective RORγt Inverse Agonist
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Qingjie Liu, Mary T. Obermeier, John S. Sack, Carolyn A. Weigelt, Georgia Cornelius, Percy H. Carter, David J. Shuster, Luisa Salter-Cid, Aberra Fura, Virna Borowski, Jingwu Duan, Purnima Khandelwal, Qing Shi, Robert J. Cherney, Cornelius Lyndon A M, Jinhong Wang, Jenny Xie, Max Ruzanov, Kevin Stefanski, Rex Denton, T. G. Murali Dhar, David Marcoux, Shiuhang Yip, Melissa Yarde, Douglas G. Batt, Javed Khan, Joseph A. Tino, Qihong Zhao, Anurag S. Srivastava, Arvind Mathur, Mary Ellen Cvijic, John E. Macor, Sha Li, and Dauh-Rurng Wu
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chemistry.chemical_classification ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Inflammation ,Acanthosis ,Pharmacology ,medicine.disease ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Bioavailability ,010404 medicinal & biomolecular chemistry ,Pharmacokinetics ,Pharmacodynamics ,Drug Discovery ,medicine ,Inverse agonist ,medicine.symptom ,Whole blood ,Tricyclic - Abstract
[Image: see text] Novel tricyclic analogues were designed, synthesized, and evaluated as RORγt inverse agonists. Several of these compounds were potent in an IL-17 human whole blood assay and exhibited excellent oral bioavailability in mouse pharmacokinetic studies. This led to the identification of compound 5, which displayed dose-dependent inhibition of IL-17F production in a mouse IL-2/IL-23 stimulated pharmacodynamic model. In addition, compound 5 was studied in mouse acanthosis and imiquimod-induced models of skin inflammation, where it demonstrated robust efficacy comparable to a positive control. As a result of this excellent overall profile, compound 5 (BMS-986251) was selected as a clinically viable developmental candidate.
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- 2020
23. Discovery and characterization of N-(1,3-dialkyl-1H-indazol-6-yl)-1H-pyrazolo[4,3-b]pyridin-3-amine scaffold as mGlu4 positive allosteric modulators that mitigate CYP1A2 induction liability
- Author
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John E. Macor, Darren W. Engers, Julie L. Engers, Colleen M. Niswender, P. Jeffrey Conn, Rocio Zamorano, Alice L. Rodriguez, Joanne J. Bronson, Sean R. Bollinger, Anna L. Blobaum, Joseph D. Panarese, Craig W. Lindsley, Alison R. Gregro, Corey R. Hopkins, Wu Yong Jin, and Megan M. Breiner
- Subjects
0301 basic medicine ,Scaffold ,Chemistry ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Allosteric regulation ,CYP1A2 ,Pharmaceutical Science ,Biochemistry ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,In vivo ,Drug Discovery ,Molecular Medicine ,Potency ,Amine gas treating ,Selectivity ,Molecular Biology ,030217 neurology & neurosurgery - Abstract
Previous reports from our laboratory disclosed the structure and activity of a novel 1H-pyrazolo[4,3-b]pyridine-3-amine scaffold (VU8506) which showed excellent potency, selectivity and in vivo efficacy in preclinical rodent models of Parkinson’s disease. Unfortunately, this compound suffered from significant CYP1A2 induction as measured through upstream AhR activation (125-fold) and thus was precluded from further advancement in chronic studies. Herein, we report a new scaffold developed recently which was systematically studied in order to mitigate the CYP1A2 liabilities presented in the earlier scaffolds. We have identified a novel structure that maintains the potency and selectivity of other mGlu4 PAMs, leading to 9i (hmGlu4 EC50 = 43 nM; AhR activation = 2.3-fold).
- Published
- 2018
24. Design and synthesis of a novel series of (1′ S ,2 R ,4′ S )-3 H -4′-azaspiro[benzo[4,5]imidazo[2,1- b ]oxazole-2,2′-bicyclo[2.2.2]octanes] with high affinity for the α7 neuronal nicotinic receptor
- Author
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Hyunsoo Park, James H. Cook, Ivar M. McDonald, Bradley C. Pearce, Matthew D. Hill, Haiquan Fang, John E. Macor, Lizbeth Gallagher, F. Christopher Zusi, Richard E. Olson, and Linda J. Bristow
- Subjects
0301 basic medicine ,alpha7 Nicotinic Acetylcholine Receptor ,Stereochemistry ,Clinical Biochemistry ,Molecular Conformation ,Convergent synthesis ,Pharmaceutical Science ,Crystallography, X-Ray ,01 natural sciences ,Biochemistry ,Bridged Bicyclo Compounds ,03 medical and health sciences ,chemistry.chemical_compound ,α7 nicotinic acetylcholine receptor ,Drug Discovery ,Humans ,Potency ,Nicotinic Agonists ,Receptor ,Molecular Biology ,Oxazole ,Bicyclic molecule ,Organic Chemistry ,Hydrogen Bonding ,Stereoisomerism ,Octanes ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,030104 developmental biology ,Nicotinic agonist ,chemistry ,Drug Design ,Molecular Medicine ,Receptors, Serotonin, 5-HT3 ,Selectivity ,Protein Binding - Abstract
We describe an efficient and convergent synthesis of a series of (1'S,2R,4'S)-3H-4'-azaspiro[benzo[4,5]imidazo[2,1-b]oxazole-2,2'-bicyclo[2.2.2]octanes] displaying potency for the α7 nicotinic acetylcholine receptor (nAChR) and good selectivity vs. the related 5-HT3A receptor.
- Published
- 2017
25. Calcitonin gene-related peptide (CGRP) receptor antagonists: Heterocyclic modification of a novel azepinone lead
- Author
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Valerie J. Whiterock, Xiang-Jun Jiang, Guanglin Luo, Carl D. Davis, Charles M. Conway, Deborah Keavy, Kimberly A. Widmann, Laura J. Signor, Walter Kostich, Ling Chen, John E. Macor, Gene M. Dubowchik, Richard Schartman, Ping Chen, and Michael Gulianello
- Subjects
Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Calcitonin gene-related peptide ,01 natural sciences ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Calcitonin Gene-Related Peptide Receptor Antagonists ,In vivo ,biology.animal ,Drug Discovery ,Humans ,Molecular Biology ,CGRP receptor ,G protein-coupled receptor ,Indazole ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,CYP3A4 ,010405 organic chemistry ,Organic Chemistry ,Marmoset ,Azepines ,0104 chemical sciences ,Bioavailability ,010404 medicinal & biomolecular chemistry ,chemistry ,Molecular Medicine ,Receptors, Calcitonin Gene-Related Peptide - Abstract
In our efforts to identify orally bioavailable CGRP receptor antagonists, we previously discovered a novel series of orally available azepinone derivatives that unfortunately also exhibited the unwanted property of potent time-dependent human CYP3A4 inhibition. Through heterocyclic replacement of the indazole ring, we discovered a series of heterocycle derivatives as high-affinity CGRP receptor antagonists. Some of them showed reasonable oral exposures, and the imidazolone derivatives that showed good oral exposure also exhibited substantially reduced time-dependent CYP3A4 inhibition. Several compounds showed strong in vivo efficacy in our marmoset facial blood flow assay with up to 87% inhibition of CGRP-induced activity. However, oral bioavailability generally remained low, emphasizing the challenges we and others encountered in discovering clinical development candidates for this difficult Class B GPCR target.
- Published
- 2021
26. Preclinical Characterization of (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169), a Novel, Intravenous, Glutamate N-Methyl-d-Aspartate 2B Receptor Negative Allosteric Modulator with Potential in Major Depressive Disorder
- Author
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Mahesh Paschapur, Jeffrey M. Brown, Tanmaya Bastia, Lawrence R. Marcin, Jayakumar Sankara Warrier, Srinivasan Thangathirupathy, Joanne J. Bronson, Raja Reddy Kallem, Huiping Zhang, Jyoti Gulia, Alda Fernandes, Digavalli V. Sivarao, Deborah Keavy, Amy Newton, Jianqing Li, Pattipati S. Naidu, Kuchibhotla Vijaya Kumar, James Kempson, Michael R. Weed, Rick L. Pieschl, Mark Bookbinder, Charlie F. Albright, Kimberly Newberry, Yu-Wen Li, Dalton King, Manjunath Ramarao, Jean Simmermacher, Linda J. Bristow, Meenakshee Sinha, Eric Shields, Lorin A. Thompson, John E. Macor, Charulatha Sanmathi, Imadul Islam, B.N. Srikumar, Richard E. Olson, John D. Graef, Arvind Mathur, Narasimharaju Kalidindi, Joseph Polino, Michael Sinz, Thaddeus F. Molski, Jayant Aher, and Reeba K. Vikramadithyan
- Subjects
0301 basic medicine ,Pharmacology ,Allosteric modulator ,Chemistry ,digestive, oral, and skin physiology ,Allosteric regulation ,Glutamate receptor ,Long-term potentiation ,Prodrug ,stomatognathic diseases ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,In vivo ,Molecular Medicine ,Receptor ,030217 neurology & neurosurgery ,Ex vivo - Abstract
(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169) and the phosphate prodrug 4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen phosphate (BMS-986163) were identified from a drug discovery effort focused on the development of novel, intravenous glutamate N-methyl-d-aspartate 2B receptor (GluN2B) negative allosteric modulators (NAMs) for treatment-resistant depression (TRD). BMS-986169 showed high binding affinity for the GluN2B subunit allosteric modulatory site (Ki = 4.03-6.3 nM) and selectively inhibited GluN2B receptor function in Xenopus oocytes expressing human N-methyl-d-aspartate receptor subtypes (IC50 = 24.1 nM). BMS-986169 weakly inhibited human ether-a-go-go-related gene channel activity (IC50 = 28.4 μM) and had negligible activity in an assay panel containing 40 additional pharmacological targets. Intravenous administration of BMS-986169 or BMS-986163 dose-dependently increased GluN2B receptor occupancy and inhibited in vivo [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ([3H]MK-801) binding, confirming target engagement and effective cleavage of the prodrug. BMS-986169 reduced immobility in the mouse forced swim test, an effect similar to intravenous ketamine treatment. Decreased novelty suppressed feeding latency, and increased ex vivo hippocampal long-term potentiation was also seen 24 hours after acute BMS-986163 or BMS-986169 administration. BMS-986169 did not produce ketamine-like hyperlocomotion or abnormal behaviors in mice or cynomolgus monkeys but did produce a transient working memory impairment in monkeys that was closely related to plasma exposure. Finally, BMS-986163 produced robust changes in the quantitative electroencephalogram power band distribution, a translational measure that can be used to assess pharmacodynamic activity in healthy humans. Due to the poor aqueous solubility of BMS-986169, BMS-986163 was selected as the lead GluN2B NAM candidate for further evaluation as a novel intravenous agent for TRD.
- Published
- 2017
27. [ 3 H]BMT-046091 a potent and selective radioligand to determine AAK1 distribution and target engagement
- Author
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Justin Vijay Louis, Kumaran Dandapani, Susheel J. Nara, Yang Hong, Yung Tian, Sarat Kumar Sarvasiddhi, Yifeng Lu, Carolyn Diane Dzierba, Walter Kostich, Yu-Wen Li, Rick L. Pieschl, Sreenivasulu Naidu, Charlie F. Albright, Joanne J. Bronson, John E. Macor, and Reeba K. Vikramadithyan
- Subjects
0301 basic medicine ,Pharmacology ,Kinase ,Central nervous system ,Biology ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Nociception ,Knockout mouse ,Radioligand ,medicine ,Phosphorylation ,Binding site ,Receptor ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Adaptor-associated kinase 1 (AAK1), a member of the Ark1/Prk1 family of serine/threonine kinases, plays a role in modulating clatherin coated endocytosis of specific surface receptors. We have demonstrated that AAK1 inhibitors are efficacious in rodent models of neuropathic pain (Kostich et al., 2016). Here we have characterized the binding properties and distribution pattern of the tritiated AAK1 radioligand, [3H]BMT-046091, in rodents and cynomolgus monkeys, and used the radioligand to measure the brain target occupancy following systemic administration of AAK1 inhibitors. We have found that [3H]BMT-046091 is potent and selective AAK1 inhibitor. It inhibits AAK1 phosphorylation of a peptide derived from a physiologic substrate, the μ2 subunit of the adaptor protein complex, with an IC50 value of 2.8 nM, and is inactive at >5 μM in a panel of functional or binding assays for receptors, transporters and enzymes. [3H]BMT-046091 binding in the brain is absent in the AAK1 knockout mouse, and is displaceable with a high concentration of AAK1 inhibitors in wild type mice. Specific [3H]BMT-046091 binding is widespread in the brain and spinal cord with the highest density in the cortex, hippocampus, amygdala, striatum and thalamus. In the spinal cord, [3H]BMT-046091 binding appears enriched in the dorsal horn superficial layers. Oral administration of LP-935509, an AAK1 inhibitor, results in a dose-dependent occupation of AAK1 binding sites in the brain and spinal cord. The increase in AAK1 binding site occupancy by LP-935509 correlates with the decrease in antinociceptive responses in the rat chronic constriction injury model of neuropathic pain.
- Published
- 2017
28. Asymmetric Synthesis of the Major Metabolite of a Calcitonin Gene-Related Peptide Receptor Antagonist and Mechanism of Epoxide Hydrogenolysis
- Author
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Gene M. Dubowchik, Benjamin M. Johnson, John E. Macor, Charles M. Conway, Guanglin Luo, Walter Kostich, Ling Chen, and Alicia Ng
- Subjects
chemistry.chemical_classification ,Ketone ,010405 organic chemistry ,Stereochemistry ,Hydrolysis ,Spectrum Analysis ,Metabolite ,Organic Chemistry ,Enantioselective synthesis ,Epoxide ,Ring (chemistry) ,Heterocyclic Compounds, 4 or More Rings ,01 natural sciences ,0104 chemical sciences ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Calcitonin gene-related peptide receptor antagonist ,chemistry ,Calcitonin Gene-Related Peptide Receptor Antagonists ,Hydrogenolysis ,Epoxy Compounds ,Cycloheptane ,030217 neurology & neurosurgery - Abstract
An asymmetric synthesis of the major metabolite of the calcitonin gene-related peptide recepotor antagonist BMS-846372 is presented. The variously substituted cyclohepta[b]pyridine ring system represents an underexplored ring system and showed some unexpected chemistry. Reactivities of epoxide and ketone functional groups on the cycloheptane ring were extensively controlled by a remote bulky TIPS group. The rate difference of the hydrogenolysis between two diastereomeric epoxide intermediates shed some light on the mechanism of epoxide hydrogenolysis, and further, deuterium labeling studies revealed more mechanistic details on this well-known chemical transformation for the first time.
- Published
- 2017
29. Synthesis and evaluation of prodrugs of corticotropin-releasing factor-1 (CRF 1 ) receptor antagonist BMS-665053 leading to improved oral bioavailability
- Author
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Joanne J. Bronson, Nicholas J. Lodge, John E. Macor, James E. Grace, Richard A. Hartz, Vivekananda M. Vrudhula, and Vijay T. Ahuja
- Subjects
010405 organic chemistry ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Crf1 receptor ,Antagonist ,Pharmaceutical Science ,Prodrug ,Pharmacology ,030226 pharmacology & pharmacy ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Bioavailability ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Drug Discovery ,Aqueous solubility ,Alkoxy group ,Molecular Medicine ,Molecular Biology ,Linker - Abstract
A series of phosphate and ester-based prodrugs of anilinopyrazinone 1 (BMS-665053) containing either a methylene or an (acyloxy)alkoxy linker was prepared and evaluated in rat pharmacokinetic studies with the goal of improving the oral bioavailability of the parent (1). The prodrugs, in general, had improved aqueous solubility and oral bioavailability compared to 1. Prodrug 12, which contains an (acyloxy)alkoxy linker, showed the greatest improvement in the oral bioavailability relative to the parent (1), with a seven-fold increase (from 5% to 36%) in rat pharmacokinetic studies.
- Published
- 2017
30. BMS-933043, a Selective α7 nAChR Partial Agonist for the Treatment of Cognitive Deficits Associated with Schizophrenia
- Author
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Regina Miller, Nicholas J. Lodge, John E. Macor, Wendy Clarke, Lizbeth Gallagher, Linda J. Bristow, Daniel G. Morgan, Christiana I. Iwuagwu, Ryan Westphal, Haiquan Fang, Kimberley A. Lentz, Debra J. Post-Munson, Amy Easton, Matthew D. Hill, Bei Wang, Robert A. Mate, Ivar M. McDonald, James H. Cook, Yulia Benitex, Dalton King, Thaddeus F. Molski, Ronald J. Knox, F. Christopher Zusi, Richard E. Olson, Rex Denton, Jingsong Fan, Rulin Zhao, and Robert Zaczek
- Subjects
0301 basic medicine ,business.industry ,Organic Chemistry ,Cognition ,Pharmacology ,medicine.disease ,Biochemistry ,Partial agonist ,03 medical and health sciences ,Nicotinic acetylcholine receptor ,030104 developmental biology ,0302 clinical medicine ,Nicotinic agonist ,In vivo ,Schizophrenia ,Drug Discovery ,medicine ,business ,Receptor ,030217 neurology & neurosurgery ,Acetylcholine ,medicine.drug - Abstract
The therapeutic treatment of negative symptoms and cognitive dysfunction associated with schizophrenia is a significant unmet medical need. Preclinical literature indicates that α7 neuronal nicotinic acetylcholine (nACh) receptor agonists may provide an effective approach to treating cognitive dysfunction in schizophrenia. We report herein the discovery and evaluation of 1c (BMS-933043), a novel and potent α7 nACh receptor partial agonist with high selectivity against other nicotinic acetylcholine receptor subtypes (>100-fold) and the 5-HT3A receptor (>300-fold). In vivo activity was demonstrated in a preclinical model of cognitive impairment, mouse novel object recognition. BMS-933043 has completed Phase I clinical trials.
- Published
- 2017
31. Development of spiroguanidine-derived α7 neuronal nicotinic receptor partial agonists
- Author
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Lizbeth Gallagher, Yulia Benitex, Matthew D. Hill, Richard E. Olson, Nicholas J. Lodge, Francine L. Healy, Debra J. Post-Munson, John E. Macor, Sivarao V. Digavalli, Daniel G. Morgan, JoAnne E Natale, Linda J. Bristow, Ping Chen, and Haiquan Fang
- Subjects
0301 basic medicine ,Quinuclidines ,alpha7 Nicotinic Acetylcholine Receptor ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,Partial agonist ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,Ganglion type nicotinic receptor ,Drug Discovery ,Enzyme-linked receptor ,Humans ,Spiro Compounds ,Receptor ,Molecular Biology ,Guanidine ,Arc (protein) ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Organic Chemistry ,Nicotinic acetylcholine receptor ,030104 developmental biology ,Nicotinic agonist ,Molecular Medicine ,Alpha-4 beta-2 nicotinic receptor ,030217 neurology & neurosurgery - Abstract
We describe the synthesis of quinuclidine-containing spiroguanidines and their utility as α7 neuronal nicotinic acetylcholine receptor (nAChR) partial agonists. The convergent synthetic route developed for this study allowed for rapid SAR investigation and provided access to a structurally diverse set of analogs. A potent and selective α7 nAChR partial agonist, N‐(6‐methyl‐1,3‐benzoxazol‐2‐yl)‐3′,5′‐dihydro‐4‐azaspiro[bicyclo[2.2.2]octane‐2,4′‐imidazole]‐2′‐amine (BMS-910731, 16), was identified. This compound induced immediate early genes c-fos and Arc in a preclinical rodent model of α7 nAChR-derived cellular activation and plasticity. Importantly, the ability to incorporate selectivity for the α7 nACh receptor over the 5-HT3A receptor in this series suggested a significant difference in steric requirements between the two receptors.
- Published
- 2017
32. Triazolopyridine ethers as potent, orally active mGlu2 positive allosteric modulators for treating schizophrenia
- Author
-
Valerie J. Whiterock, Amy Easton, Regina Miller, Lawrence R. Marcin, Meredith Ferrante, Bradley C. Pearce, John B. Hogan, Joanne J. Bronson, Clotilde Bourin, Mendi A. Higgins, Robert G. Gentles, F. Christopher Zusi, Walter Kostich, John E. Macor, Michael Gulianello, Min Ding, Linda J. Bristow, Adam Hendricson, Kim A. Johnson, Andrew Alt, Yanling Huang, and Matthew A. Seager
- Subjects
Allosteric modulator ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Plasma protein binding ,Pharmacology ,medicine.disease ,Biochemistry ,In vitro ,030227 psychiatry ,03 medical and health sciences ,0302 clinical medicine ,Oral administration ,Schizophrenia ,Drug Discovery ,Lipophilicity ,medicine ,Molecular Medicine ,Triazolopyridine ,Molecular Biology ,030217 neurology & neurosurgery - Abstract
Triazolopyridine ethers with mGlu2 positive allosteric modulator (PAM) activity are disclosed. The synthesis, in vitro activity, and metabolic stability data for a series of analogs is provided. The effort resulted in the discovery of a potent, selective, and brain penetrant lead molecule BMT-133218 ((+)-7m). After oral administration at 10mg/kg, BMT-133218 demonstrated full reversal of PCP-stimulated locomotor activity and prevented MK-801-induced working memory deficits in separate mouse models. Also, reversal of impairments in executive function were observed in rat set-shifting studies at 3 and 10mg/kg (p.o.). Extensive plasma protein binding as the result of high lipophilicity likely limited activity at lower doses. Optimized triazolopyridine ethers offer utility as mGlu2 PAMs for the treatment of schizophrenia and merit further preclinical investigation.
- Published
- 2017
33. Difluorocyclobutylacetylenes as positive allosteric modulators of mGluR5 with reduced bioactivation potential
- Author
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Andrew P. Degnan, Valerie J. Whiterock, Darrell Maxwell, Umesh Hanumegowda, Digavalli V. Sivarao, Anand Balakrishnan, Eric Shields, Joanne J. Bronson, Jeffrey M. Brown, Ryan Westphal, Amy Easton, Arun K. Senapati, Xiaoliang Zhuo, John E. Macor, Kenneth S. Santone, Michael Gulianello, Regina Miller, and Melissa Hill-Drzewi
- Subjects
0301 basic medicine ,Pyridines ,Receptor, Metabotropic Glutamate 5 ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,Compound 32 ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,Allosteric Regulation ,mental disorders ,Drug Discovery ,Animals ,Humans ,Novel object recognition ,Receptor ,Molecular Biology ,Oxazolidinones ,Brain uptake ,Dose-Response Relationship, Drug ,Molecular Structure ,Metabotropic glutamate receptor 5 ,Chemistry ,Organic Chemistry ,Rats ,030104 developmental biology ,nervous system ,Molecular Medicine ,NMDA receptor ,Function (biology) - Abstract
Schizophrenia is a serious illness that affects millions of patients and has been associated with N-methyl-d-aspartate receptor (NMDAR) hypofunction. It has been demonstrated that activation of metabotropic glutamate receptor 5 (mGluR5) enhances NMDA receptor function, suggesting the potential utility of mGluR5 positive allosteric modulators (PAMs) in the treatment of schizophrenia. Herein we describe the optimization of an mGluR5 PAM by replacement of a phenyl with aliphatic heterocycles and carbocycles as a strategy to reduce bioactivation in a biaryl acetylene chemotype. Replacement with a difluorocyclobutane followed by further optimization culminated in the identification of compound 32, a low fold shift PAM with reduced bioactivation potential. Compound 32 demonstrated favorable brain uptake and robust efficacy in mouse novel object recognition (NOR) at low doses.
- Published
- 2016
34. Discovery of Indazoles as Potent, Orally Active Dual Neurokinin 1 Receptor Antagonists and Serotonin Transporter Inhibitors for the Treatment of Depression
- Author
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Amy Newton, Joanna Hu, Thorsten Rosner, George O. Tora, Yu-Wen Li, Joseph Raybon, Yi Hsiao, Xiaoping Hou, Joanne J. Bronson, Nicholas J. Lodge, John E. Macor, David A. Conlon, Carl D. Davis, Jung-Hui Sun, Michael K. Wong, Kevin W. Gillman, Sarah J. Taylor, Umesh Hanumegowda, Rudolph G. Krause, Huiping Zhang, Hong Huang, Matthew T. Taber, Andrew P. Degnan, and Rick L. Pieschl
- Subjects
0301 basic medicine ,Indazoles ,Physiology ,Cognitive Neuroscience ,hERG ,Drug Evaluation, Preclinical ,Administration, Oral ,Pharmacology ,Biochemistry ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,Neurokinin-1 Receptor Antagonists ,Transcriptional Regulator ERG ,In vivo ,Drug Discovery ,Animals ,Humans ,Serotonin Uptake Inhibitors ,Receptor ,Serotonin transporter ,Serotonin Plasma Membrane Transport Proteins ,Depressive Disorder ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Drug discovery ,Chemistry ,Cell Biology ,General Medicine ,Receptors, Neurokinin-1 ,Antidepressive Agents ,Rats ,Disease Models, Animal ,030104 developmental biology ,biology.protein ,Gerbillinae ,Reuptake inhibitor ,Selective Serotonin Reuptake Inhibitors ,030217 neurology & neurosurgery - Abstract
Combination studies of neurokinin 1 (NK1) receptor antagonists and serotonin-selective reuptake inhibitors (SSRIs) have shown promise in preclinical models of depression. Such a combination may offer important advantages over the current standard of care. Herein we describe the discovery and optimization of an indazole-based chemotype to provide a series of potent dual NK1 receptor antagonists/serotonin transporter (SERT) inhibitors to overcome issues of ion channel blockade. This effort culminated in the identification of compound 9, an analogue that demonstrated favorable oral bioavailability, excellent brain uptake, and robust in vivo efficacy in a validated depression model. Over the course of this work, a novel heterocycle-directed asymmetric hydrogenation was developed to facilitate installation of the key stereogenic center.
- Published
- 2016
35. Development of 1H-Pyrazolo[3,4-b]pyridines as Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators
- Author
-
Valerie J. Whiterock, John E. Macor, Joanne J. Bronson, Melissa Hill-Drzewi, Regina Miller, Lizbeth Gallagher, Thaddeus F. Molski, Amy Easton, Xiaoliang Zhuo, Matthew D. Hill, Andrew P. Degnan, Xiaojun Han, Jeffrey M. Brown, Robert L. Bertekap, Haiquan Fang, Michael Gulianello, Michele Matchett, Kenneth S. Santone, and Anand Balakrishnan
- Subjects
0301 basic medicine ,010405 organic chemistry ,Metabotropic glutamate receptor 5 ,Metabotropic glutamate receptor 4 ,Organic Chemistry ,Allosteric regulation ,Metabotropic glutamate receptor 7 ,Pharmacology ,Biology ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,03 medical and health sciences ,030104 developmental biology ,mental disorders ,Drug Discovery ,NMDA receptor ,Metabotropic glutamate receptor 1 ,Metabotropic glutamate receptor 3 ,Metabotropic glutamate receptor 2 ,Neuroscience - Abstract
The metabotropic glutamate receptor 5 (mGluR5) is an attractive target for the treatment of schizophrenia due to its role in regulating glutamatergic signaling in association with the N-methyl-d-aspartate receptor (NMDAR). We describe the synthesis of 1H-pyrazolo[3,4-b]pyridines and their utility as mGluR5 positive allosteric modulators (PAMs) without inherent agonist activity. A facile and convergent synthetic route provided access to a structurally diverse set of analogues that contain neither the aryl-acetylene-aryl nor aryl-methyleneoxy-aryl elements, the predominant structural motifs described in the literature. Binding studies suggest that members of our new chemotype do not engage the receptor at the MPEP and CPPHA mGluR5 allosteric sites. SAR studies culminated in the first non-MPEP site PAM, 1H-pyrazolo[3,4-b]pyridine 31 (BMT-145027), to improve cognition in a preclinical rodent model of learning and memory.
- Published
- 2016
36. Discovery of Branebrutinib (BMS-986195): A Strategy for Identifying a Highly Potent and Selective Covalent Inhibitor Providing Rapid in Vivo Inactivation of Bruton's Tyrosine Kinase (BTK)
- Author
-
Richard Rampulla, Stacey Skala, Charu Chaudhry, Percy H. Carter, Alban Allentoff, Tracy L. Taylor, Ling Li, Andrew J. Tebben, Luisa Salter-Cid, Aberra Fura, Rulin Zhao, Ian M. Catlett, Richard A. Westhouse, Myra Beaudoin Bertrand, John E. Macor, Robin Moore, Celia D’Arienzo, Matt Pokross, Douglas G. Batt, Scott H. Watterson, Mary T. Obermeier, Qingjie Liu, Daniel Smith, Lorell Discenza, Michael Galella, Jun Dai, Arvind Mathur, Kathleen M. Gillooly, Elizabeth M. Heimrich, Jianqing Li, Zheng Yang, Michael Wallace, Kim W. McIntyre, James R. Burke, Mark A. Pattoli, Joseph A. Tino, Lihong Cheng, Naiyu Zheng, Rodney Vickery, Claudine Pulicicchio, Yifan Zhang, Qian Ruan, and Paul A. Elzinga
- Subjects
Indoles ,B-cell receptor ,01 natural sciences ,Arthritis, Rheumatoid ,03 medical and health sciences ,Inhibitory Concentration 50 ,Mice ,Piperidines ,immune system diseases ,In vivo ,hemic and lymphatic diseases ,Drug Discovery ,Agammaglobulinaemia Tyrosine Kinase ,Bruton's tyrosine kinase ,Animals ,Humans ,Lupus Erythematosus, Systemic ,Receptor ,Protein Kinase Inhibitors ,030304 developmental biology ,0303 health sciences ,biology ,Dose-Response Relationship, Drug ,Kinase ,Drug discovery ,Chemistry ,breakpoint cluster region ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Macaca fascicularis ,Cancer research ,biology.protein ,Molecular Medicine ,Tyrosine kinase - Abstract
Bruton’s tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fce receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.
- Published
- 2019
37. Synthesis of functionalized derivatives of the gamma-secretase modulator BMS-932481 and identification of its major metabolite
- Author
-
John E. Macor, Benjamin M. Johnson, Richard E. Olson, Rex Denton, Michael K. Ahlijanian, Charles F. Albright, Yong-Jin Wu, Antonio Ramirez, Jeremy H. Toyn, Lorin A. Thompson, Xiaoliang Zhuo, Yunhui Zhang, and Kenneth M. Boy
- Subjects
Pyrimidine ,Metabolite ,education ,Clinical Biochemistry ,Pharmaceutical Science ,Alcohol ,01 natural sciences ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,In vivo ,Drug Discovery ,Animals ,Humans ,Molecular Biology ,Gamma secretase ,Aniline Compounds ,Dose-Response Relationship, Drug ,Molecular Structure ,Bicyclic molecule ,010405 organic chemistry ,digestive, oral, and skin physiology ,Organic Chemistry ,In vitro ,Rats ,0104 chemical sciences ,stomatognathic diseases ,010404 medicinal & biomolecular chemistry ,Pyrimidines ,chemistry ,Microsomes, Liver ,Microsome ,Molecular Medicine ,Amyloid Precursor Protein Secretases - Abstract
In an effort to improve physical properties by introducing polar functionality into the bicyclic pyrimidine gamma-secretase modulator (GSM) clinical candidate BMS-932481, we prepared several oxidative products of BMS-932481. Among the analogs that were prepared, the C-5 alcohol 3 was identified as the predominant metabolite of BMS-932481 found in rat and human liver microsomes. Alcohol 3 was determined to be chemically unstable, leading to the hypothesis that 3 may lead to the production of reactive species both in vitro and in vivo.
- Published
- 2020
38. Synthesis and evaluation of carbamate and aryl ether substituted pyrazinones as corticotropin releasing factor-1 (CRF1) receptor antagonists
- Author
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Kimberley A. Lentz, Gail K. Mattson, James E. Grace, Nicholas J. Lodge, John E. Macor, Richard A. Hartz, Thaddeus F. Molski, Vijay T. Ahuja, and Joanne J. Bronson
- Subjects
Carbamate ,Stereochemistry ,Chemistry ,Aryl ,medicine.medical_treatment ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Ether ,030226 pharmacology & pharmacy ,Biochemistry ,In vitro ,Corticotropin-releasing hormone receptor 1 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Discovery ,medicine ,Molecular Medicine ,Structure–activity relationship ,Receptor ,Molecular Biology ,IC50 ,030217 neurology & neurosurgery - Abstract
A series of pyrazinone-based compounds incorporating either carbamate or aryl ether groups was synthesized and evaluated as corticotropin-releasing factor-1 (CRF1) receptor antagonists. Structure-activity relationship studies led to the identification of highly potent CRF1 receptor antagonists 14a (IC50=0.74 nM) and 14b (IC50=1.9 nM). The synthesis, structure-activity relationships and in vitro metabolic stability properties of compounds in this series will be described.
- Published
- 2016
39. Robust Translation of -Secretase Modulator Pharmacology across Preclinical Species and Human Subjects
- Author
-
John Morrison, Kenneth M. Boy, Alan S. Robertson, Malaz AbuTarif, Jeremy H. Toyn, Valerie Guss, Xiaoliang Zhuo, Maciej Gasior, James E. Grace, Cong Wei, Jun-Sheng Wang, Quan Hong, Joseph Raybon, Lynda S. Cook, Nina Hoque, Richard E. Olson, Wendy Clarke, Rex Denton, Lorin A. Thompson, Francis Sweeney, Flora Berisha, Jere E. Meredith, Dieter M. Drexler, Holly Soares, Kimberly A. Lentz, Charlie F. Albright, Ramesh Padmanabha, Michael J. Furlong, John E. Macor, Michael K. Ahlijanian, Dmitry Zuev, and Kimberly Snow
- Subjects
Bridged-Ring Compounds ,0301 basic medicine ,Drug Evaluation, Preclinical ,Peptide ,Pharmacology ,Cell Line ,Rats, Sprague-Dawley ,Drug Discovery and Translational Medicine ,03 medical and health sciences ,Dogs ,0302 clinical medicine ,Species Specificity ,Pharmacokinetics ,In vivo ,Animals ,Humans ,Tissue Distribution ,chemistry.chemical_classification ,Amyloid beta-Peptides ,Aniline Compounds ,Dose-Response Relationship, Drug ,Receptors, Notch ,biology ,Brain ,Translation (biology) ,Biological activity ,Small molecule ,In vitro ,Macaca fascicularis ,Pyrimidines ,030104 developmental biology ,chemistry ,biology.protein ,Molecular Medicine ,Female ,Amyloid Precursor Protein Secretases ,Amyloid precursor protein secretase ,030217 neurology & neurosurgery - Abstract
The amyloid-β peptide (Aβ)-in particular, the 42-amino acid form, Aβ1-42-is thought to play a key role in the pathogenesis of Alzheimer's disease (AD). Thus, several therapeutic modalities aiming to inhibit Aβ synthesis or increase the clearance of Aβ have entered clinical trials, including γ-secretase inhibitors, anti-Aβ antibodies, and amyloid-β precursor protein cleaving enzyme inhibitors. A unique class of small molecules, γ-secretase modulators (GSMs), selectively reduce Aβ1-42 production, and may also decrease Aβ1-40 while simultaneously increasing one or more shorter Aβ peptides, such as Aβ1-38 and Aβ1-37. GSMs are particularly attractive because they do not alter the total amount of Aβ peptides produced by γ-secretase activity; they spare the processing of other γ-secretase substrates, such as Notch; and they do not cause accumulation of the potentially toxic processing intermediate, β-C-terminal fragment. This report describes the translation of pharmacological activity across species for two novel GSMs, (S)-7-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (BMS-932481) and (S,Z)-17-(4-chloro-2-fluorophenyl)-34-(3-methyl-1H-1,2,4-triazol-1-yl)-16,17-dihydro-15H-4-oxa-2,9-diaza-1(2,4)-cyclopenta[d]pyrimidina-3(1,3)-benzenacyclononaphan-6-ene (BMS-986133). These GSMs are highly potent in vitro, exhibit dose- and time-dependent activity in vivo, and have consistent levels of pharmacological effect across rats, dogs, monkeys, and human subjects. In rats, the two GSMs exhibit similar pharmacokinetics/pharmacodynamics between the brain and cerebrospinal fluid. In all species, GSM treatment decreased Aβ1-42 and Aβ1-40 levels while increasing Aβ1-38 and Aβ1-37 by a corresponding amount. Thus, the GSM mechanism and central activity translate across preclinical species and humans, thereby validating this therapeutic modality for potential utility in AD.
- Published
- 2016
40. Biochemical and behavioral effects of PDE10A inhibitors: Relationship to target site occupancy
- Author
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Nicholas J. Lodge, John E. Macor, Matthew A. Seager, Samuel Gerritz, Shaun Langdon, Robert Zaczek, Joanne J. Bronson, Alda Fernandes, Karen Heman, James R. Merritt, Yuan Tian, Ryan Westphal, Yang Hong, Annapurna Pendri, Lizbeth Gallagher, Trevor Wojcik, Chongwu Zhang, Yu-Wen Li, and Thaddeus F. Molski
- Subjects
Male ,0301 basic medicine ,Phosphodiesterase Inhibitors ,Striatum ,Pharmacology ,Hippocampal formation ,Medium spiny neuron ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Basal ganglia ,Radioligand ,Animals ,Binding site ,Mice, Knockout ,Binding Sites ,Behavior, Animal ,Dose-Response Relationship, Drug ,Phosphoric Diester Hydrolases ,Chemistry ,Brain ,Phosphodiesterase ,Macaca fascicularis ,030104 developmental biology ,PDE10A ,030217 neurology & neurosurgery ,Antipsychotic Agents - Abstract
Phosphodiesterase 10A (PDE10A) inhibitors increase the functionality of striatal medium spiny neurons and produce antipsychotic-like effects in rodents by blocking PDE10A mediated hydrolysis of cAMP and/or cGMP. In the current study, we characterized a radiolabeled PDE10A inhibitor, [(3)H]BMS-843496, and developed an ex vivo PDE10 binding autoradiographic assay to explore the relationship between PDE10 binding site occupancy and the observed biochemical and behavioral effects of PDE10 inhibitors in mice. [(3)H]BMS-843496 is a potent PDE10A inhibitor with a binding affinity (KD) of 0.15 nM and a functional selectivity of >100-fold over other PDE subtypes tested. Specific [(3)H]BMS-843496 binding sites were dominant in the basal ganglia, especially the striatum, with low to moderate binding in the cortical and hippocampal areas, of the mouse and monkey brain. Systemic administration of PDE10 inhibitors produced a dose- and plasma/brain concentration-dependent increase in PDE10A occupancy measured in the striatum. PDE10A occupancy was positively correlated with striatal pCREB expression levels. PDE10A occupancy was also correlated with antipsychotic-like effects measured using the conditioned avoidance response model; a minimum of ∼40% occupancy was typically required to achieve efficacy. In contrast, a clear relationship between PDE10A occupancy and catalepsy scores, a potential extrapyramidal symptom readout in rodent, was not evident.
- Published
- 2016
41. Design and optimization of tricyclic gamma-secretase modulators
- Author
-
Dmitry Zuev, Richard E. Olson, Jeremy H. Toyn, Jianliang Shi, Lorin A. Thompson, Kimberley A. Lentz, Xu Li, John E. Macor, and James E. Grace
- Subjects
Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,macromolecular substances ,01 natural sciences ,Biochemistry ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,Drug Discovery ,Animals ,Humans ,Protease Inhibitors ,Molecular Biology ,Gamma secretase ,chemistry.chemical_classification ,Aniline Compounds ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Triazines ,Chemistry ,musculoskeletal, neural, and ocular physiology ,Organic Chemistry ,Combinatorial chemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,nervous system ,Drug Design ,biology.protein ,Molecular Medicine ,Amyloid Precursor Protein Secretases ,Amyloid precursor protein secretase ,030217 neurology & neurosurgery ,Tricyclic - Abstract
Beginning with a diaminotriazine screening hit, several series of novel, tricyclic gamma-secretase modulators (GSMs) were designed. The SAR of several related series of GSMs is presented, and the in vivo profile of a lead molecule from the series is described.
- Published
- 2016
42. Synthesis of pyrimido[4,5- c ]azepine- and pyrimido[4,5- c ]oxepine-based γ-secretase modulators
- Author
-
Lorin A. Thompson, Yunhui Zhang, Jeremy H. Toyn, John E. Macor, and Yong-Jin Wu
- Subjects
Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Metathesis ,01 natural sciences ,Biochemistry ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Discovery ,Humans ,Molecule ,Structure–activity relationship ,γ secretase ,Azepine ,Molecular Biology ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,010405 organic chemistry ,Organic Chemistry ,Azepines ,Combinatorial chemistry ,0104 chemical sciences ,Pyrimidines ,chemistry ,Oxepins ,biology.protein ,Molecular Medicine ,Amyloid Precursor Protein Secretases ,Amyloid precursor protein secretase ,030217 neurology & neurosurgery - Abstract
This Letter describes an efficient ring-closing metathesis approach to 2-chloro-4-amino-pyrimido[4,5-c]azepines and 2-chloro-4-amino-pyrimido[4,5-c]oxepines. These chlorides were applied to the synthesis of several potent γ-secretase modulators (GSMs).
- Published
- 2016
43. Discovery of Isonicotinamides as Highly Selective, Brain Penetrable, and Orally Active Glycogen Synthase Kinase-3 Inhibitors
- Author
-
Matt Pokross, Jonathan Lippy, Guanglin Luo, Vinod Arora, Hong Xiao, Nengyin Liu, John E. Macor, Joseph Raybon, Wendy Clarke, Catherine R. Burton, David R. Langley, Carol M. Krause, Gene M. Dubowchik, Yang Cao, Ling Chen, Hal A. Lewis, Kimberly Snow, Prasanna Sivaprakasam, and Kevin Kish
- Subjects
Models, Molecular ,Niacinamide ,0301 basic medicine ,Transgene ,Administration, Oral ,Mice, Transgenic ,Pharmacology ,Crystallography, X-Ray ,Serine ,Glycogen Synthase Kinase 3 ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,GSK-3 ,Drug Discovery ,Animals ,Humans ,Structure–activity relationship ,Threonine ,Protein Kinase Inhibitors ,GSK3B ,Glycogen Synthase Kinase 3 beta ,Dose-Response Relationship, Drug ,Molecular Structure ,Drug discovery ,Chemistry ,Kinase ,Brain ,Mice, Inbred C57BL ,030104 developmental biology ,Biochemistry ,Molecular Medicine - Abstract
GSK-3 is a serine/threonine kinase that has numerous substrates. Many of these proteins are involved in the regulation of diverse cellular functions, including metabolism, differentiation, proliferation, and apoptosis. Inhibition of GSK-3 may be useful in treating a number of diseases including Alzheimer's disease (AD), type II diabetes, mood disorders, and some cancers, but the approach poses significant challenges. Here, we present a class of isonicotinamides that are potent, highly kinase-selective GSK-3 inhibitors, the members of which demonstrated oral activity in a triple-transgenic mouse model of AD. The remarkably high kinase selectivity and straightforward synthesis of these compounds bode well for their further exploration as tool compounds and therapeutics.
- Published
- 2016
44. Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents
- Author
-
Alicia Ng, Andrea McClure, Chiehying Chang, Fukang Yang, Hyunsoo Park, Yong-Jin Wu, Jason M. Guernon, Jianliang Shi, John E. Macor, Charles F. Albright, Ramkumar Rajamani, Michael K. Ahlijanian, Lorin A. Thompson, Jeremy H. Toyn, Lawrence B. Snyder, Hal A. Lewis, and Dan Camac
- Subjects
0301 basic medicine ,biology ,010405 organic chemistry ,Chemistry ,medicine.drug_class ,Organic Chemistry ,Active site ,Carboxamide ,Inhibitory postsynaptic potential ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Biochemistry of Alzheimer's disease ,Glutamine ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,mental disorders ,Drug Discovery ,biology.protein ,medicine ,Threonine ,Lead compound ,IC50 - Abstract
By targeting the flap backbone of the BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved BACE1 inhibitory activity over the lead compound 1. The cocrystal structure of 18 bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine-carboxamide 26 as a very potent BACE1 inhibitor (IC50 < 1 nM). This compound demonstrated robust brain Aβ reduction in rat dose–response studies. Thus, compound 26 may be useful in testing the amyloid hypothesis of Alzheimer’s disease.
- Published
- 2016
45. Asymmetric Synthesis of Heterocyclic Analogues of a CGRP Receptor Antagonist for Treating Migraine
- Author
-
Charles M. Conway, Gene M. Dubowchik, John E. Macor, Walter Kostich, Guanglin Luo, and Ling Chen
- Subjects
Molecular Structure ,Pyrazine ,Pyridines ,Stereochemistry ,Migraine Disorders ,Aryl ,Organic Chemistry ,Enantioselective synthesis ,Diastereomer ,Stereoisomerism ,Biochemistry ,chemistry.chemical_compound ,Piperidines ,chemistry ,Calcitonin Gene-Related Peptide Receptor Antagonists ,Heck reaction ,Cycloheptanes ,Physical and Theoretical Chemistry ,Thiazole ,Cycloheptane - Abstract
An asymmetric synthesis of novel heterocyclic analogue of the CGRP receptor antagonist rimegepant (BMS-927711, 3) is reported. The cycloheptane ring was constructed by an intramolecular Heck reaction. The application of Hayashi-Miyaura and Ellman reactions furnished the aryl and the amine chiral centers, while the separable diastereomeric third chiral center alcohols led to both carbamate and urea analogues. This synthetic approach was applicable to both 6- and 5-membered heterocycles as exemplified by pyrazine and thiazole derivatives.
- Published
- 2015
46. Macrocyclic prolinyl acyl guanidines as inhibitors of β-secretase (BACE)
- Author
-
Andrew C. Good, Joe Shi, Catherine R. Burton, Samuel Gerritz, John E. Macor, Weixu Zhai, Shirong Zhu, Richard E. Olson, Jeremy H. Toyn, James E. Grace, Donna M. Barten, Yunhui Zhang, Jere E. Meredith, Kimberley A. Lentz, Lorin A. Thompson, Yong-Jin Wu, Charles F. Albright, Jason M. Guernon, and Kenneth M. Boy
- Subjects
Male ,Macrocyclic Compounds ,Proline ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Cathepsin E ,Cathepsin D ,Guanidines ,Biochemistry ,Madin Darby Canine Kidney Cells ,Mice ,chemistry.chemical_compound ,Dogs ,In vivo ,Drug Discovery ,Animals ,Aspartic Acid Endopeptidases ,Humans ,Potency ,Protease Inhibitors ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Guanidine ,Molecular Biology ,chemistry.chemical_classification ,Isothiazole ,Amyloid beta-Peptides ,biology ,Chemotype ,Organic Chemistry ,Pepsin A ,Molecular Docking Simulation ,Enzyme ,chemistry ,biology.protein ,Molecular Medicine ,Efflux ,Amyloid Precursor Protein Secretases ,Caco-2 Cells ,Amyloid precursor protein secretase - Abstract
The synthesis, evaluation, and structure-activity relationships of a class of acyl guanidines which inhibit the BACE-1 enzyme are presented. The prolinyl acyl guanidine chemotype (7c), unlike compounds of the parent isothiazole chemotype (1), yielded compounds with good agreement between their enzymatic and cellular potency as well as a reduced susceptibility to P-gp efflux. Further improvements in potency and P-gp ratio were realized via a macrocyclization strategy. The in vivo profile in wild-type mice and P-gp effects for the macrocyclic analog 21c is presented.
- Published
- 2015
47. Discovery of furo[2,3- d ][1,3]thiazinamines as beta amyloid cleaving enzyme-1 (BACE1) inhibitors
- Author
-
Charles F. Albright, Yong-Jin Wu, Chiehying Chang, Jason M. Guernon, Michael K. Ahlijanian, Dan Camac, Jeremy H. Toyn, John E. Macor, Lorin A. Thompson, Jodi K. Muckelbauer, and Ramkumar Rajamani
- Subjects
Models, Molecular ,0301 basic medicine ,Amyloid ,Stereochemistry ,Clinical Biochemistry ,Thiazines ,Pharmaceutical Science ,01 natural sciences ,Biochemistry ,D-1 ,03 medical and health sciences ,chemistry.chemical_compound ,Alzheimer Disease ,Thiazine ,Catalytic Domain ,Amide ,Drug Discovery ,Hydrolase ,Aspartic Acid Endopeptidases ,Humans ,Enzyme Inhibitors ,Furans ,Molecular Biology ,chemistry.chemical_classification ,biology ,010405 organic chemistry ,Organic Chemistry ,Active site ,0104 chemical sciences ,030104 developmental biology ,Enzyme ,chemistry ,biology.protein ,Molecular Medicine ,Bioisostere ,Amyloid Precursor Protein Secretases ,Protein Binding - Abstract
This Letter describes the synthesis and structure-activity relationships of a series of furo[2,3-d][1,3]thiazinamine BACE1 inhibitors. The co-crystal structure of a representative thiazinamine 2e bound with the BACE1 active site displayed a binding mode driven by interactions with the catalytic aspartate dyad and engagement of the biaryl amide toward the S1 and S3 pockets. This work indicates that furo[2,3-d]thiazine can serve as a viable bioisostere of the known furo[3,4-d]thiazine.
- Published
- 2016
48. The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu
- Author
-
Joseph D, Panarese, Darren W, Engers, Yong-Jin, Wu, Jason M, Guernon, Aspen, Chun, Alison R, Gregro, Aaron M, Bender, Rory A, Capstick, Joshua M, Wieting, Joanne J, Bronson, John E, Macor, Ryan, Westphal, Matthew, Soars, Julie E, Engers, Andrew S, Felts, Alice L, Rodriguez, Kyle A, Emmitte, Carrie K, Jones, Anna L, Blobaum, P Jeffrey, Conn, Colleen M, Niswender, Corey R, Hopkins, and Craig W, Lindsley
- Subjects
Structure-Activity Relationship ,Allosteric Regulation ,Dose-Response Relationship, Drug ,Molecular Structure ,Drug Discovery ,Humans ,Isoquinolines ,Receptors, Metabotropic Glutamate ,Heterocyclic Compounds, 2-Ring ,Myotonin-Protein Kinase - Abstract
This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu
- Published
- 2018
49. Discovery and characterization of N-(1,3-dialkyl-1H-indazol-6-yl)-1H-pyrazolo[4,3-b]pyridin-3-amine scaffold as mGlu
- Author
-
Darren W, Engers, Sean R, Bollinger, Julie L, Engers, Joseph D, Panarese, Megan M, Breiner, Alison, Gregro, Anna L, Blobaum, Joanne J, Bronson, Yong-Jin, Wu, John E, Macor, Alice L, Rodriguez, Rocio, Zamorano, P Jeffrey, Conn, Craig W, Lindsley, Colleen M, Niswender, and Corey R, Hopkins
- Subjects
Antiparkinson Agents ,Structure-Activity Relationship ,Allosteric Regulation ,Cytochrome P-450 CYP1A2 ,Pyridines ,Enzyme Induction ,Cytochrome P-450 CYP1A2 Inducers ,Drug Discovery ,Animals ,Humans ,Pyrazoles ,Receptors, Metabotropic Glutamate ,Rats - Abstract
Previous reports from our laboratory disclosed the structure and activity of a novel 1H-pyrazolo[4,3-b]pyridine-3-amine scaffold (VU8506) which showed excellent potency, selectivity and in vivo efficacy in preclinical rodent models of Parkinson's disease. Unfortunately, this compound suffered from significant CYP1A2 induction as measured through upstream AhR activation (125-fold) and thus was precluded from further advancement in chronic studies. Herein, we report a new scaffold developed recently which was systematically studied in order to mitigate the CYP1A2 liabilities presented in the earlier scaffolds. We have identified a novel structure that maintains the potency and selectivity of other mGlu
- Published
- 2018
50. BMS-986163, a Negative Allosteric Modulator of GluN2B with Potential Utility in Major Depressive Disorder
- Author
-
Arvind Mathur, Rajareddy Kallem, Thaddeus F. Molski, Manjunatha Narayana Rao Kamble, Michelle Nophsker, Huiping Zhang, Murali Subramanian, Dalton King, Linda J. Bristow, Lawrence R. Marcin, B.N. Srikumar, Grandhi Venkat Ram Krishna Mohan Gupta, Kumar Kuchibhotla Vijaya, Jayakumar Sankara Warrier, Michael Sinz, Charulatha Sanmathi, G. Nagaraju, Xiaoliang Zhuo, Raju Mannoori, Imadul Islam, Alicia Ng, Pattipati S. Naidu, Eric Shields, Joanne J. Bronson, Narasimharaju Kalidindi, Reeba K. Vikramadithyan, Gopikishan Tonukunuru, Lorin A. Thompson, James Kempson, Srinivasan Thangathirupathy, Jogi Srinivas, Bradley C. Pearce, Jyoti Gulia, Jean Simmermacher, Srinivas Cheruku, Mahesh Paschapur, Jianliang Shi, John E. Macor, Jayant Aher, Manjunath Ramarao, Charlie F. Albright, Richard E. Olson, Rex Denton, Aliphedi B. Reddy, Hyunsoo Park, Karageorge George N, Tanmaya Bastia, and Jianqing Li
- Subjects
0301 basic medicine ,Allosteric modulator ,Chemistry ,Organic Chemistry ,Allosteric regulation ,Pharmacology ,Prodrug ,medicine.disease ,Biochemistry ,In vitro ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,In vivo ,Drug Discovery ,medicine ,Major depressive disorder ,IC50 ,030217 neurology & neurosurgery ,Ex vivo - Abstract
[Image: see text] There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the N-methyl-d-aspartate receptor subtype GluN2B have demonstrated encouraging therapeutic potential. We report herein the discovery and preclinical profile of a water-soluble intravenous prodrug BMS-986163 (6) and its active parent molecule BMS-986169 (5), which demonstrated high binding affinity for the GluN2B allosteric site (K(i) = 4.0 nM) and selective inhibition of GluN2B receptor function (IC(50) = 24 nM) in cells. The conversion of prodrug 6 to parent 5 was rapid in vitro and in vivo across preclinical species. After intravenous administration, compounds 5 and 6 have exhibited robust levels of ex vivo GluN2B target engagement in rodents and antidepressant-like activity in mice. No significant off-target activity was observed for 5, 6, or the major circulating metabolites met-1 and met-2. The prodrug BMS-986163 (6) has demonstrated an acceptable safety and toxicology profile and was selected as a preclinical candidate for further evaluation in major depressive disorder.
- Published
- 2018
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