32 results on '"Weinstein DS"'
Search Results
2. Determining competence in estimating energy needs.
- Author
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Weinstein DS, Skipper A, Vanek VW, and Synder D
- Published
- 1998
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3. Prodrug Strategy to Address Impaired Oral Absorption of a Weakly Basic TYK2 Inhibitor Caused by a Gastric Acid-Reducing Agent.
- Author
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A M Subbaiah M, Ramar T, Reddy M, Sivaprasad Lvj S, Yeshwante S, Sridhar S, Desai S, Chiney M, Dierks EA, Mathur A, Moslin R, and Weinstein DS
- Subjects
- Animals, Administration, Oral, Rats, Hydrogen-Ion Concentration, Male, Gastric Acid metabolism, Rats, Sprague-Dawley, Solubility, Pentagastrin pharmacology, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors pharmacokinetics, Protein Kinase Inhibitors chemistry, Humans, Macaca fascicularis, Drug Interactions, Prodrugs pharmacology, Prodrugs chemistry, Famotidine pharmacology, TYK2 Kinase antagonists & inhibitors, TYK2 Kinase metabolism
- Abstract
The pH-dependent solubility of the weakly basic TYK2 inhibitor 1 posed a risk to its advancement, given that drugs with such profiles have exhibited drug-drug interaction (DDI) with stomach acid-reducing agents in humans. In a rat model of pH dependence, preadministration of famotidine caused a 2.4-fold lower exposure of 1 when compared to control rats, implying that pH-dependent oral absorption can reduce the active drug's exposure and translate to subtherapeutic treatment. As part of risk mitigation, a prodrug strategy was explored by synthesizing solubility-enhancing prodrugs, resulting in the identification of lead prodrug 3c with acceptable stability and solubility profiles. In rats, the prodrug eliminated the significant difference in AUC and C
max between pentagastrin and famotidine arms, thereby effectively mitigating the impaired drug absorption at the elevated pH relevant for absorption and DDI with famotidine. The prodrug also facilitated dose-proportional systemic exposure of 1 following dose escalation in rats and monkeys.- Published
- 2024
- Full Text
- View/download PDF
4. Author Correction: Chemoproteomic discovery of a covalent allosteric inhibitor of WRN helicase.
- Author
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Baltgalvis KA, Lamb KN, Symons KT, Wu CC, Hoffman MA, Snead AN, Song X, Glaza T, Kikuchi S, Green JC, Rogness DC, Lam B, Rodriguez-Aguirre ME, Woody DR, Eissler CL, Rodiles S, Negron SM, Bernard SM, Tran E, Pollock J, Tabatabaei A, Contreras V, Williams HN, Pastuszka MK, Sigler JJ, Pettazzoni P, Rudolph MG, Classen M, Brugger D, Claiborne C, Plancher JM, Cuartas I, Seoane J, Burgess LE, Abraham RT, Weinstein DS, Simon GM, Patricelli MP, and Kinsella TM
- Published
- 2024
- Full Text
- View/download PDF
5. Chemoproteomic discovery of a covalent allosteric inhibitor of WRN helicase.
- Author
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Baltgalvis KA, Lamb KN, Symons KT, Wu CC, Hoffman MA, Snead AN, Song X, Glaza T, Kikuchi S, Green JC, Rogness DC, Lam B, Rodriguez-Aguirre ME, Woody DR, Eissler CL, Rodiles S, Negron SM, Bernard SM, Tran E, Pollock J, Tabatabaei A, Contreras V, Williams HN, Pastuszka MK, Sigler JJ, Pettazzoni P, Rudolph MG, Classen M, Brugger D, Claiborne C, Plancher JM, Cuartas I, Seoane J, Burgess LE, Abraham RT, Weinstein DS, Simon GM, Patricelli MP, and Kinsella TM
- Subjects
- Animals, Female, Humans, Male, Mice, Cell Line, Tumor, Colorectal Neoplasms drug therapy, Colorectal Neoplasms enzymology, Colorectal Neoplasms pathology, Cysteine drug effects, Cysteine metabolism, DNA Breaks, Double-Stranded drug effects, Microsatellite Instability, Models, Molecular, Xenograft Model Antitumor Assays, Cell Death drug effects, Adenosine Triphosphate metabolism, Allosteric Regulation drug effects, Drug Discovery methods, Enzyme Inhibitors pharmacology, Enzyme Inhibitors chemistry, Proteomics, Werner Syndrome Helicase antagonists & inhibitors, Werner Syndrome Helicase chemistry, Werner Syndrome Helicase metabolism
- Abstract
WRN helicase is a promising target for treatment of cancers with microsatellite instability (MSI) due to its essential role in resolving deleterious non-canonical DNA structures that accumulate in cells with faulty mismatch repair mechanisms
1-5 . Currently there are no approved drugs directly targeting human DNA or RNA helicases, in part owing to the challenging nature of developing potent and selective compounds to this class of proteins. Here we describe the chemoproteomics-enabled discovery of a clinical-stage, covalent allosteric inhibitor of WRN, VVD-133214. This compound selectively engages a cysteine (C727) located in a region of the helicase domain subject to interdomain movement during DNA unwinding. VVD-133214 binds WRN protein cooperatively with nucleotide and stabilizes compact conformations lacking the dynamic flexibility necessary for proper helicase function, resulting in widespread double-stranded DNA breaks, nuclear swelling and cell death in MSI-high (MSI-H), but not in microsatellite-stable, cells. The compound was well tolerated in mice and led to robust tumour regression in multiple MSI-H colorectal cancer cell lines and patient-derived xenograft models. Our work shows an allosteric approach for inhibition of WRN function that circumvents competition from an endogenous ATP cofactor in cancer cells, and designates VVD-133214 as a promising drug candidate for patients with MSI-H cancers., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2024
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6. Structure-activity relationship study of central pyridine-derived TYK2 JH2 inhibitors: Optimization of the PK profile through C4' and C6 variations.
- Author
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Xiao Z, Yang MG, Liu C, Sherwood T, Gilmore JL, Lin J, Li P, Wu DR, Tokarski J, Li S, Cheng L, Xie C, Fan J, Dierks E, Strnad J, Cvijic ME, Khan J, Ruzanov M, Galella M, Khandelwal P, Dyckman AJ, Mathur A, Lombardo LJ, Macor JE, Carter PH, Aranibar N, Burke JR, and Weinstein DS
- Subjects
- Mice, Animals, Structure-Activity Relationship, TYK2 Kinase, Pyridines pharmacology
- Abstract
Efforts directed at improving potency and preparing structurally different TYK2 JH2 inhibitors from the first generation of compounds such as 1a led to the SAR study of new central pyridyl based analogs 2-4. The current SAR study resulted in the identification of 4h as a potent and selective TYK2 JH2 inhibitor with distinct structural differences from 1a. In this manuscript, the in vitro and in vivo profiles of 4h are described. The hWB IC
50 of 4h was shown as 41 nM with 94% bioavailability in the mouse PK study., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)- Published
- 2023
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7. DCAF11 Supports Targeted Protein Degradation by Electrophilic Proteolysis-Targeting Chimeras.
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Zhang X, Luukkonen LM, Eissler CL, Crowley VM, Yamashita Y, Schafroth MA, Kikuchi S, Weinstein DS, Symons KT, Nordin BE, Rodriguez JL, Wucherpfennig TG, Bauer LG, Dix MM, Stamos D, Kinsella TM, Simon GM, Baltgalvis KA, and Cravatt BF
- Subjects
- Cell Line, Tumor, Humans, Male, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Proteasome Endopeptidase Complex metabolism, Proteolysis, Receptors, Androgen metabolism, Ubiquitin metabolism, Ubiquitin-Protein Ligase Complexes metabolism, Ubiquitin-Protein Ligase Complexes physiology
- Abstract
Ligand-induced protein degradation has emerged as a compelling approach to promote the targeted elimination of proteins from cells by directing these proteins to the ubiquitin-proteasome machinery. So far, only a limited number of E3 ligases have been found to support ligand-induced protein degradation, reflecting a dearth of E3-binding compounds for proteolysis-targeting chimera (PROTAC) design. Here, we describe a functional screening strategy performed with a focused library of candidate electrophilic PROTACs to discover bifunctional compounds that degrade proteins in human cells by covalently engaging E3 ligases. Mechanistic studies revealed that the electrophilic PROTACs act through modifying specific cysteines in DCAF11, a poorly characterized E3 ligase substrate adaptor. We further show that DCAF11-directed electrophilic PROTACs can degrade multiple endogenous proteins, including FBKP12 and the androgen receptor, in human prostate cancer cells. Our findings designate DCAF11 as an E3 ligase capable of supporting ligand-induced protein degradation via electrophilic PROTACs.
- Published
- 2021
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8. Discovery of BMS-986202: A Clinical Tyk2 Inhibitor that Binds to Tyk2 JH2.
- Author
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Liu C, Lin J, Langevine C, Smith D, Li J, Tokarski JS, Khan J, Ruzanov M, Strnad J, Zupa-Fernandez A, Cheng L, Gillooly KM, Shuster D, Zhang Y, Thankappan A, McIntyre KW, Chaudhry C, Elzinga PA, Chiney M, Chimalakonda A, Lombardo LJ, Macor JE, Carter PH, Burke JR, and Weinstein DS
- Subjects
- Animals, Catalysis, Crystallography, X-Ray, Cyclopropanes chemistry, Humans, Mice, Oxazoles chemistry, Protein Binding, Protein Kinase Inhibitors chemistry, Psoriasis drug therapy, Structure-Activity Relationship, TYK2 Kinase metabolism, Cyclopropanes pharmacology, Drug Discovery, Oxazoles pharmacology, Protein Kinase Inhibitors pharmacology, TYK2 Kinase antagonists & inhibitors
- 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.
- Published
- 2021
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9. Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165.
- Author
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Wrobleski ST, Moslin R, Lin S, Zhang Y, Spergel S, Kempson J, Tokarski JS, Strnad J, Zupa-Fernandez A, Cheng L, Shuster D, Gillooly K, Yang X, Heimrich E, McIntyre KW, Chaudhry C, Khan J, Ruzanov M, Tredup J, Mulligan D, Xie D, Sun H, Huang C, D'Arienzo C, Aranibar N, Chiney M, Chimalakonda A, Pitts WJ, Lombardo L, Carter PH, Burke JR, and Weinstein DS
- Subjects
- Allosteric Regulation drug effects, Animals, Crystallography, X-Ray, Heterocyclic Compounds chemistry, Heterocyclic Compounds pharmacokinetics, Heterocyclic Compounds therapeutic use, Humans, Mice, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacokinetics, Protein Kinase Inhibitors therapeutic use, Autoimmune Diseases drug therapy, Drug Discovery, Heterocyclic Compounds pharmacology, Protein Kinase Inhibitors pharmacology, TYK2 Kinase antagonists & inhibitors
- Abstract
Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective JAK inhibitors that traditionally target the catalytically active site of this kinase family has been a formidable challenge. Our strategy to achieve high selectivity for TYK2 relies on targeting the TYK2 pseudokinase (JH2) domain. Herein we report the late stage optimization efforts including a structure-guided design and water displacement strategy that led to the discovery of BMS-986165 ( 11 ) as a high affinity JH2 ligand and potent allosteric inhibitor of TYK2. In addition to unprecedented JAK isoform and kinome selectivity, 11 shows excellent pharmacokinetic properties with minimal profiling liabilities and is efficacious in several murine models of autoimmune disease. On the basis of these findings, 11 appears differentiated from all other reported JAK inhibitors and has been advanced as the first pseudokinase-directed therapeutic in clinical development as an oral treatment for autoimmune diseases.
- Published
- 2019
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10. Identification of N -Methyl Nicotinamide and N -Methyl Pyridazine-3-Carboxamide Pseudokinase Domain Ligands as Highly Selective Allosteric Inhibitors of Tyrosine Kinase 2 (TYK2).
- Author
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Moslin R, Zhang Y, Wrobleski ST, Lin S, Mertzman M, Spergel S, Tokarski JS, Strnad J, Gillooly K, McIntyre KW, Zupa-Fernandez A, Cheng L, Sun H, Chaudhry C, Huang C, D'Arienzo C, Heimrich E, Yang X, Muckelbauer JK, Chang C, Tredup J, Mulligan D, Xie D, Aranibar N, Chiney M, Burke JR, Lombardo L, Carter PH, and Weinstein DS
- Subjects
- Allosteric Regulation, Animals, Humans, Ligands, Mice, Niacinamide metabolism, Niacinamide pharmacology, Nicotinic Acids metabolism, Protein Kinase Inhibitors metabolism, Structure-Activity Relationship, Niacinamide analogs & derivatives, Nicotinic Acids pharmacology, Protein Kinase Inhibitors pharmacology, TYK2 Kinase antagonists & inhibitors
- Abstract
As a member of the Janus (JAK) family of nonreceptor tyrosine kinases, TYK2 plays an important role in mediating the signaling of pro-inflammatory cytokines including IL-12, IL-23, and type 1 interferons. The nicotinamide 4 , identified by a SPA-based high-throughput screen targeting the TYK2 pseudokinase domain, potently inhibits IL-23 and IFNα signaling in cellular assays. The described work details the optimization of this poorly selective hit ( 4 ) to potent and selective molecules such as 47 and 48 . The discoveries described herein were critical to the eventual identification of the clinical TYK2 JH2 inhibitor (see following report in this issue). Compound 48 provided robust inhibition in a mouse IL-12-induced IFNγ pharmacodynamic model as well as efficacy in an IL-23 and IL-12-dependent mouse colitis model. These results demonstrate the ability of TYK2 JH2 domain binders to provide a highly selective alternative to conventional TYK2 orthosteric inhibitors.
- Published
- 2019
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11. Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain.
- Author
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Burke JR, Cheng L, Gillooly KM, Strnad J, Zupa-Fernandez A, Catlett IM, Zhang Y, Heimrich EM, McIntyre KW, Cunningham MD, Carman JA, Zhou X, Banas D, Chaudhry C, Li S, D'Arienzo C, Chimalakonda A, Yang X, Xie JH, Pang J, Zhao Q, Rose SM, Huang J, Moslin RM, Wrobleski ST, Weinstein DS, and Salter-Cid LM
- Subjects
- Animals, Female, Healthy Volunteers, Heterocyclic Compounds pharmacology, Humans, Interferon alpha-2 pharmacology, Mice, Mice, Inbred C57BL, Mice, SCID, Protein Kinase Inhibitors pharmacology, TYK2 Kinase antagonists & inhibitors, Autoimmunity drug effects, Signal Transduction drug effects, TYK2 Kinase chemistry
- Abstract
TYK2 is a nonreceptor tyrosine kinase involved in adaptive and innate immune responses. A deactivating coding variant has previously been shown to prevent receptor-stimulated activation of this kinase and provides high protection from several common autoimmune diseases but without immunodeficiency. An agent that recapitulates the phenotype of this deactivating coding variant may therefore represent an important advancement in the treatment of autoimmunity. BMS-986165 is a potent oral agent that similarly blocks receptor-stimulated activation of TYK2 allosterically and with high selectivity and potency afforded through optimized binding to a regulatory domain of the protein. Signaling and functional responses in human T
H 17, TH 1, B cells, and myeloid cells integral to autoimmunity were blocked by BMS-986165, both in vitro and in vivo in a phase 1 clinical trial. BMS-986165 demonstrated robust efficacy, consistent with blockade of multiple autoimmune pathways, in murine models of lupus nephritis and inflammatory bowel disease, supporting its therapeutic potential for multiple immune-mediated diseases., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2019
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12. Identification of Imidazo[1,2- b ]pyridazine Derivatives as Potent, Selective, and Orally Active Tyk2 JH2 Inhibitors.
- Author
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Liu C, Lin J, Moslin R, Tokarski JS, Muckelbauer J, Chang C, Tredup J, Xie D, Park H, Li P, Wu DR, Strnad J, Zupa-Fernandez A, Cheng L, Chaudhry C, Chen J, Chen C, Sun H, Elzinga P, D'arienzo C, Gillooly K, Taylor TL, McIntyre KW, Salter-Cid L, Lombardo LJ, Carter PH, Aranibar N, Burke JR, and Weinstein DS
- Abstract
In sharp contrast to a previously reported series of 6-anilino imidazopyridazine based Tyk2 JH2 ligands, 6-((2-oxo- N 1-substituted-1,2-dihydropyridin-3-yl)amino)imidazo[1,2- b ]pyridazine analogs were found to display dramatically improved metabolic stability. The N1-substituent on 2-oxo-1,2-dihydropyridine ring can be a variety of alkyl, aryl, and heteroaryl groups, but among them, 2-pyridyl provided much enhanced Caco-2 permeability, attributed to its ability to form intramolecular hydrogen bonds. Further structure-activity relationship studies at the C3 position led to the identification of highly potent and selective Tyk2 JH2 inhibitor 6 , which proved to be highly effective in inhibiting IFNγ production in a rat pharmacodynamics model and fully efficacious in a rat adjuvant arthritis model., Competing Interests: The authors declare no competing financial interest.
- Published
- 2019
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13. Identification of bicyclic hexafluoroisopropyl alcohol sulfonamides as retinoic acid receptor-related orphan receptor gamma (RORγ/RORc) inverse agonists. Employing structure-based drug design to improve pregnane X receptor (PXR) selectivity.
- Author
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Gong H, Weinstein DS, Lu Z, Duan JJ, Stachura S, Haque L, Karmakar A, Hemagiri H, Raut DK, Gupta AK, Khan J, Camac D, Sack JS, Pudzianowski A, Wu DR, Yarde M, Shen DR, Borowski V, Xie JH, Sun H, D'Arienzo C, Dabros M, Galella MA, Wang F, Weigelt CA, Zhao Q, Foster W, Somerville JE, Salter-Cid LM, Barrish JC, Carter PH, and Dhar TGM
- Subjects
- Animals, Bridged Bicyclo Compounds chemical synthesis, Bridged Bicyclo Compounds chemistry, Crystallography, X-Ray, Dose-Response Relationship, Drug, Humans, Liver X Receptors agonists, Male, Mice, Mice, Inbred BALB C, Models, Molecular, Molecular Structure, Pregnane X Receptor, Propanols chemical synthesis, Propanols chemistry, Structure-Activity Relationship, Sulfonamides chemical synthesis, Sulfonamides chemistry, Retinoic Acid Receptor gamma, Bridged Bicyclo Compounds pharmacology, Drug Design, Propanols pharmacology, Receptors, Retinoic Acid agonists, Receptors, Steroid agonists, Sulfonamides pharmacology
- Abstract
We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Y
max in the PXR assay for long term preclinical pharmacokinetic (PK) studies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2018
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14. Identification of imidazo[1,2- b ]pyridazine TYK2 pseudokinase ligands as potent and selective allosteric inhibitors of TYK2 signalling.
- Author
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Moslin R, Gardner D, Santella J, Zhang Y, Duncia JV, Liu C, Lin J, Tokarski JS, Strnad J, Pedicord D, Chen J, Blat Y, Zupa-Fernandez A, Cheng L, Sun H, Chaudhry C, Huang C, D'Arienzo C, Sack JS, Muckelbauer JK, Chang C, Tredup J, Xie D, Aranibar N, Burke JR, Carter PH, and Weinstein DS
- Abstract
As a member of the Janus (JAK) family of non-receptor tyrosine kinases, TYK2 mediates the signaling of pro-inflammatory cytokines including IL-12, IL-23 and type 1 interferon (IFN), and therefore represents an attractive potential target for treating the various immuno-inflammatory diseases in which these cytokines have been shown to play a role. Following up on our previous report that ligands to the pseudokinase domain (JH2) of TYK2 suppress cytokine-mediated receptor activation of the catalytic (JH1) domain, the imidazo[1,2- b ]pyridazine (IZP) 7 was identified as a promising hit compound. Through iterative modification of each of the substituents of the IZP scaffold, the cellular potency was improved while maintaining selectivity over the JH1 domain. These studies led to the discovery of the JH2-selective TYK2 inhibitor 29 , which provided encouraging systemic exposures after oral dosing in mice. Phosphodiesterase 4 (PDE4) was identified as an off-target and potential liability of the IZP ligands, and selectivity for TYK2 JH2 over this enzyme was obtained by elaborating along selectivity vectors determined from analyses of X-ray co-crystal structures of representative ligands of the IZP class bound to both proteins.
- Published
- 2016
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15. In Second Year Of Marketplaces, New Entrants, ACA 'Co-Ops,' And Medicaid Plans Restrain Average Premium Growth Rates.
- Author
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Gabel JR, Whitmore H, Green M, Stromberg ST, Weinstein DS, and Oran R
- Subjects
- Blue Cross Blue Shield Insurance Plans economics, Humans, Multivariate Analysis, United States, Insurance, Health economics, Medicaid economics, Patient Protection and Affordable Care Act
- Abstract
Premiums for health insurance plans offered through the federally facilitated and state-based Marketplaces remained steady or increased only modestly from 2014 to 2015. We used data from the Marketplaces, state insurance departments, and insurer websites to examine patterns of premium pricing and the factors behind these patterns. Our data came from 2,964 unique plans offered in 2014 and 4,153 unique plans offered in 2015 in forty-nine states and the District of Columbia. Using descriptive and multivariate analysis, we found that the addition of a carrier in a rating area lowered average premiums for the two lowest-cost silver plans and the lowest-cost bronze plan by 2.2 percent. When all plans in a rating area were included, an additional carrier was associated with an average decline in premiums of 1.4 percent. Plans in the Consumer Operated and Oriented Plan Program and Medicaid managed care plans had lower premiums and average premium increases than national commercial and Blue Cross and Blue Shield plans. On average, premiums fell by an appreciably larger amount for catastrophic and bronze plans than for gold plans, and premiums for platinum plans increased. This trend of low premium increases overall is unlikely to continue, however, as insurers are faced with mounting medical claims., (Project HOPE—The People-to-People Health Foundation, Inc.)
- Published
- 2015
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16. Improving the pharmacokinetic and CYP inhibition profiles of azaxanthene-based glucocorticoid receptor modulators-identification of (S)-5-(2-(9-fluoro-2-(4-(2-hydroxypropan-2-yl)phenyl)-5H-chromeno[2,3-b]pyridin-5-yl)-2-methylpropanamido)-N-(tetrahydro-2H-pyran-4-yl)-1,3,4-thiadiazole-2-carboxamide (BMS-341).
- Author
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Yang MG, Dhar TG, Xiao Z, Xiao HY, Duan JJ, Jiang B, Galella MA, Cunningham M, Wang J, Habte S, Shuster D, McIntyre KW, Carman J, Holloway DA, Somerville JE, Nadler SG, Salter-Cid L, Barrish JC, and Weinstein DS
- Subjects
- Animals, Blood drug effects, Blood metabolism, Chemistry Techniques, Synthetic, Cytochrome P-450 CYP3A, Cytochrome P-450 CYP3A Inhibitors chemistry, Cytochrome P-450 CYP3A Inhibitors pharmacology, Cytochrome P-450 Enzyme Inhibitors chemistry, Cytochrome P-450 Enzyme Inhibitors pharmacokinetics, Disease Models, Animal, Dogs, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical methods, Drug Stability, Heterocyclic Compounds, 3-Ring chemistry, Heterocyclic Compounds, 3-Ring pharmacokinetics, Humans, Male, Rats, Inbred Lew, Receptors, Glucocorticoid agonists, Structure-Activity Relationship, Thiadiazoles chemistry, Thiadiazoles pharmacokinetics, Transcription Factor AP-1 metabolism, Arthritis, Experimental drug therapy, Cytochrome P-450 Enzyme Inhibitors pharmacology, Heterocyclic Compounds, 3-Ring pharmacology, Receptors, Glucocorticoid metabolism, Thiadiazoles pharmacology
- Abstract
An empirical approach to improve the microsomal stability and CYP inhibition profile of lead compounds 1a and 1b led to the identification of 5 (BMS-341) as a dissociated glucocorticoid receptor modulator. Compound 5 showed significant improvements in pharmacokinetic properties and, unlike compounds 1a-b, displayed a linear, dose-dependent pharmacokinetic profile in rats. When tested in a chronic model of adjuvant-induced arthritis in rat, the ED50 of 5 (0.9 mg/kg) was superior to that of both 1a and 1b (8 and 17 mg/kg, respectively).
- Published
- 2015
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17. Tyrosine Kinase 2-mediated Signal Transduction in T Lymphocytes Is Blocked by Pharmacological Stabilization of Its Pseudokinase Domain.
- Author
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Tokarski JS, Zupa-Fernandez A, Tredup JA, Pike K, Chang C, Xie D, Cheng L, Pedicord D, Muckelbauer J, Johnson SR, Wu S, Edavettal SC, Hong Y, Witmer MR, Elkin LL, Blat Y, Pitts WJ, Weinstein DS, and Burke JR
- Subjects
- Crystallography, X-Ray, Enzyme Stability, Humans, Janus Kinase 1 genetics, Janus Kinase 1 metabolism, Janus Kinase 3 genetics, Janus Kinase 3 metabolism, Protein Structure, Tertiary, Receptors, Interleukin-2 genetics, Receptors, Interleukin-2 metabolism, Receptors, Thrombopoietin genetics, Receptors, Thrombopoietin metabolism, TYK2 Kinase genetics, Models, Molecular, Signal Transduction, T-Lymphocytes enzymology, TYK2 Kinase chemistry
- Abstract
Inhibition of signal transduction downstream of the IL-23 receptor represents an intriguing approach to the treatment of autoimmunity. Using a chemogenomics approach marrying kinome-wide inhibitory profiles of a compound library with the cellular activity against an IL-23-stimulated transcriptional response in T lymphocytes, a class of inhibitors was identified that bind to and stabilize the pseudokinase domain of the Janus kinase tyrosine kinase 2 (Tyk2), resulting in blockade of receptor-mediated activation of the adjacent catalytic domain. These Tyk2 pseudokinase domain stabilizers were also shown to inhibit Tyk2-dependent signaling through the Type I interferon receptor but not Tyk2-independent signaling and transcriptional cellular assays, including stimulation through the receptors for IL-2 (JAK1- and JAK3-dependent) and thrombopoietin (JAK2-dependent), demonstrating the high functional selectivity of this approach. A crystal structure of the pseudokinase domain liganded with a representative example showed the compound bound to a site analogous to the ATP-binding site in catalytic kinases with features consistent with high ligand selectivity. The results support a model where the pseudokinase domain regulates activation of the catalytic domain by forming receptor-regulated inhibitory interactions. Tyk2 pseudokinase stabilizers, therefore, represent a novel approach to the design of potent and selective agents for the treatment of autoimmunity., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2015
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18. Discovery of acylurea isosteres of 2-acylaminothiadiazole in the azaxanthene series of glucocorticoid receptor agonists.
- Author
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Gong H, Yang M, Xiao Z, Doweyko AM, Cunningham M, Wang J, Habte S, Holloway D, Burke C, Shuster D, Gao L, Carman J, Somerville JE, Nadler SG, Salter-Cid L, Barrish JC, and Weinstein DS
- Subjects
- Crystallography, X-Ray, Dose-Response Relationship, Drug, Heterocyclic Compounds, 3-Ring chemical synthesis, Heterocyclic Compounds, 3-Ring chemistry, Humans, Models, Molecular, Molecular Structure, Stereoisomerism, Structure-Activity Relationship, Thiadiazoles chemistry, Urea analogs & derivatives, Urea chemistry, Drug Discovery, Heterocyclic Compounds, 3-Ring pharmacology, Receptors, Glucocorticoid agonists, Thiadiazoles pharmacology, Urea pharmacology
- Abstract
Acylureas and acyclic imides are found to be excellent isosteres for 2-acylamino-1,3,4-thiadiazole in the azaxanthene-based series of glucocorticoid receptor (GR) agonists. The results reported herein show that primary acylureas maintain high affinity and selectivity for GR while providing improved CYP450 inhibition and pharmacokinetic profile over 2-acylamino-1,3,4-thiadiazoles. General methods for synthesis of a variety of acylureas and acyclic imides from a carboxylic acid were utilized and are described., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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19. Azaxanthene based selective glucocorticoid receptor modulators: design, synthesis, and pharmacological evaluation of (S)-4-(5-(1-((1,3,4-thiadiazol-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-5H-chromeno[2,3-b]pyridin-2-yl)-2-fluoro-N,N-dimethylbenzamide (BMS-776532) and its methylene homologue (BMS-791826).
- Author
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Weinstein DS, Gong H, Doweyko AM, Cunningham M, Habte S, Wang JH, Holloway DA, Burke C, Gao L, Guarino V, Carman J, Somerville JE, Shuster D, Salter-Cid L, Dodd JH, Nadler SG, and Barrish JC
- Subjects
- Alkaline Phosphatase biosynthesis, Animals, Anti-Inflammatory Agents, Non-Steroidal chemistry, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Arthritis, Experimental drug therapy, Cell Line, Tumor, Drug Partial Agonism, Edema drug therapy, Glutamate-Ammonia Ligase biosynthesis, Heterocyclic Compounds, 3-Ring chemistry, Heterocyclic Compounds, 3-Ring pharmacology, Humans, In Vitro Techniques, Interleukin-1beta blood, Male, Models, Molecular, Rats, Rats, Inbred Lew, Rats, Sprague-Dawley, Receptors, Glucocorticoid genetics, Receptors, Glucocorticoid metabolism, Response Elements, Stereoisomerism, Structure-Activity Relationship, Thiadiazoles chemistry, Thiadiazoles pharmacology, Transcription Factor AP-1 genetics, Transcription Factor AP-1 metabolism, Transcriptional Activation, Tumor Necrosis Factor-alpha blood, Tyrosine Transaminase biosynthesis, Anti-Inflammatory Agents, Non-Steroidal chemical synthesis, Heterocyclic Compounds, 3-Ring chemical synthesis, Receptors, Glucocorticoid agonists, Thiadiazoles chemical synthesis
- Abstract
Structurally novel 5H-chromeno[2,3-b]pyridine (azaxanthene) selective glucocorticoid receptor (GR) modulators have been identified. A screening paradigm utilizing cellular assays of GR-mediated transrepression of proinflammatory transcription factors and transactivation of GR-dependent genes combined with three physiologically relevant assays of cytokine induction in human whole blood has allowed for the identification of high affinity, selective GR ligands that display a broad range of pharmacological profiles. Agonist efficacy in reporter assays can be tuned by halogenation of a pendent phenyl ring and correlates well with efficacy for cytokine inhibition in human whole blood. A hypothetical binding mode is proposed, invoking an expanded ligand binding pocket resembling that of arylpyrazole-bound GR structures. Two compounds of close structural similarity (35 and 37; BMS-776532 and BMS-791826, respectively) have been found to maintain distinct and consistent levels of partial agonist efficacy across several assays, displaying anti-inflammatory activity comparable to that of prednisolone 2 in suppressing cytokine production in whole blood and in rodent models of acute and chronic inflammation.
- Published
- 2011
- Full Text
- View/download PDF
20. Pyrazole-based sulfonamide and sulfamides as potent inhibitors of mammalian 15-lipoxygenase.
- Author
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Ngu K, Weinstein DS, Liu W, Langevine C, Combs DW, Zhuang S, Chen X, Madsen CS, Harper TW, Ahmad S, and Robl JA
- Subjects
- Amides chemical synthesis, Amides pharmacology, Animals, Arachidonate 15-Lipoxygenase metabolism, CHO Cells, Cricetinae, Cricetulus, Humans, Hydroxyeicosatetraenoic Acids blood, Lipoxygenase Inhibitors chemical synthesis, Lipoxygenase Inhibitors pharmacology, Rabbits, Structure-Activity Relationship, Sulfonamides chemical synthesis, Sulfonamides chemistry, Sulfonamides pharmacology, Amides chemistry, Arachidonate 15-Lipoxygenase chemistry, Lipoxygenase Inhibitors chemistry, Pyrazoles chemistry
- Abstract
A series of inhibitors of mammalian 15-lipoxygenase (15-LO) based on a 3,4,5-tri-substituted pyrazole scaffold is described. Replacement of a sulfonamide functionality in the lead series with a sulfamide group resulted in improved physicochemical properties generating analogs with enhanced inhibition in cell-based and whole blood assays., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
21. Dimethyl-diphenyl-propanamide derivatives as nonsteroidal dissociated glucocorticoid receptor agonists.
- Author
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Yang BV, Weinstein DS, Doweyko LM, Gong H, Vaccaro W, Huynh T, Xiao HY, Doweyko AM, McKay L, Holloway DA, Somerville JE, Habte S, Cunningham M, McMahon M, Townsend R, Shuster D, Dodd JH, Nadler SG, and Barrish JC
- Subjects
- Amides chemistry, Animals, Models, Molecular, Rats, Amides pharmacology, Receptors, Glucocorticoid agonists
- Abstract
A series of 2,2-dimethyl-3,3-diphenyl-propanamides as novel glucocorticoid receptor modulators is reported. SAR exploration led to the identification of 4-hydroxyphenyl propanamide derivatives displaying good agonist activity in GR-mediated transrepression assays and reduced agonist activity in GR-mediated transactivation assays. Compounds 17 and 30 showed anti-inflammatory activity comparable to prednisolone in the rat carrageenan-induced paw edema model, with markedly decreased side effects with regard to increases in blood glucose and expression of hepatic tyrosine aminotransferase. A hypothetical binding mode accounting for the induction of the functional activity by a 4-hydroxyl group is proposed.
- Published
- 2010
- Full Text
- View/download PDF
22. Discovery of novel dihydro-9,10-ethano-anthracene carboxamides as glucocorticoid receptor modulators.
- Author
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Yang BV, Vaccaro W, Doweyko AM, Doweyko LM, Huynh T, Tortolani D, Nadler SG, McKay L, Somerville J, Holloway DA, Habte S, Weinstein DS, and Barrish JC
- Subjects
- Anthracenes chemistry, Cell Line, Crystallography, X-Ray, Glucocorticoids chemistry, Glucocorticoids pharmacology, Humans, Protein Binding drug effects, Protein Binding physiology, Receptors, Glucocorticoid agonists, Receptors, Glucocorticoid physiology, Structure-Activity Relationship, Anthracenes pharmacology, Drug Discovery methods, Receptors, Glucocorticoid metabolism
- Abstract
A series of dihydro-9,10-ethano-anthracene-11-carboxamides as novel glucocorticoid receptor modulators is reported. SAR exploration identified compounds from this series displaying a promising dissociation profile in discriminating between transrepression and transactivation activities. 17a is a partial agonist of GR-mediated transactivation which elicits potent and efficacious transrepression in reporter gene assays. A hypothetical binding mode is provided which accounts for the induction of functional activity by a bridgehead methyl group.
- Published
- 2009
- Full Text
- View/download PDF
23. Discovery of selective imidazole-based inhibitors of mammalian 15-lipoxygenase: highly potent against human enzyme within a cellular environment.
- Author
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Weinstein DS, Liu W, Ngu K, Langevine C, Combs DW, Zhuang S, Chen C, Madsen CS, Harper TW, and Robl JA
- Subjects
- Animals, CHO Cells, Cricetinae, Cricetulus, Humans, Imidazoles chemistry, Male, Rats, Rats, Sprague-Dawley, Imidazoles pharmacology, Lipoxygenase Inhibitors chemistry, Lipoxygenase Inhibitors pharmacology
- Abstract
A series of 2,4,5-tri-substituted imidazoles has proven to be highly potent in inhibiting mammalian 15-lipoxygenase (15-LO) with excellent selectivity over human isozymes 5- and P-12-LO. Non-symmetrical sulfamides (e.g., 21a-n) were found to be suitable replacements for the earlier arylsulfonamide-containing members of this series (e.g., 2, 14a-p). Several members of these series also demonstrated potent inhibition of human 15-LO in a cell-based assay.
- Published
- 2007
- Full Text
- View/download PDF
24. Tryptamine and homotryptamine-based sulfonamides as potent and selective inhibitors of 15-lipoxygenase.
- Author
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Weinstein DS, Liu W, Gu Z, Langevine C, Ngu K, Fadnis L, Combs DW, Sitkoff D, Ahmad S, Zhuang S, Chen X, Wang FL, Loughney DA, Atwal KS, Zahler R, Macor JE, Madsen CS, and Murugesan N
- Subjects
- Animals, Enzyme Inhibitors chemistry, Molecular Structure, Structure-Activity Relationship, Sulfonamides chemistry, Enzyme Inhibitors pharmacology, Lipoxygenase Inhibitors, Sulfonamides pharmacology, Tryptamines chemistry
- Abstract
A series of inhibitors of mammalian 15-lipoxygenase based on tryptamine and homotryptamine scaffolds is described. Compounds with aryl substituents at C-2 of the indole core of tryptamine and homotryptamine sulfonamides (e.g., 37a-p) proved to be potent inhibitors of the isolated enzyme. Selected compounds also demonstrated desirable inhibition selectivities over isozymes 5- and P-12-LO.
- Published
- 2005
- Full Text
- View/download PDF
25. Aminoimidazoles as bioisosteres of acylguanidines: novel, potent, selective and orally bioavailable inhibitors of the sodium hydrogen exchanger isoform-1.
- Author
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Ahmad S, Ngu K, Combs DW, Wu SC, Weinstein DS, Liu W, Chen BC, Chandrasena G, Dorso CR, Kirby M, and Atwal KS
- Subjects
- Administration, Oral, Biological Availability, Cation Transport Proteins metabolism, Cell Line, Guanidines chemistry, Guanidines pharmacokinetics, Humans, Imidazoles chemistry, Imidazoles pharmacokinetics, Membrane Proteins metabolism, Protein Isoforms antagonists & inhibitors, Protein Isoforms metabolism, Sodium-Hydrogen Exchanger 1, Sodium-Hydrogen Exchangers metabolism, Stereoisomerism, Cation Transport Proteins antagonists & inhibitors, Guanidines administration & dosage, Imidazoles administration & dosage, Membrane Proteins antagonists & inhibitors, Sodium-Hydrogen Exchangers antagonists & inhibitors
- Abstract
Inhibition of the sodium hydrogen exchanger isoform-1 (NHE-1) has been shown to limit damage to the myocardium under ischemic conditions in animals. While most known NHE-1 inhibitors are acylguanidines, this report describes the design and synthesis of a series of heterocyclic inhibitors of NHE-1 including aminoimidazoles with undiminished in vitro activity and oral bioavailability.
- Published
- 2004
- Full Text
- View/download PDF
26. Radiologic diagnosis of benign esophageal strictures: a pattern approach.
- Author
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Luedtke P, Levine MS, Rubesin SE, Weinstein DS, and Laufer I
- Subjects
- Barium Sulfate therapeutic use, Diagnostic Imaging methods, Esophageal Stenosis etiology, Esophagoscopy methods, Humans, Radiography, Esophageal Stenosis diagnosis, Esophageal Stenosis diagnostic imaging
- Abstract
Benign esophageal strictures are a leading cause of dysphagia. Therefore, radiologists have an important role in detecting esophageal strictures and determining their cause. The most common cause of strictures in the distal esophagus is gastroesophageal reflux disease. Reflux-induced ("peptic") strictures may be associated with sacculations, fixed transverse folds, or esophageal intramural pseudodiverticula. In addition, scleroderma, nasogastric intubation, Zollinger-Ellison syndrome, and alkaline reflux esophagitis may be associated with stricture formation in the distal esophagus. Upper and midesophageal strictures may be caused by Barrett esophagus, mediastinal irradiation, ingestion of drugs or caustic substances, congenital esophageal stenosis, skin diseases, or esophageal intramural pseudodiverticulosis. Other unusual causes of esophageal stricture formation include Crohn disease, Candida esophagitis, graft-versus-host disease, eosinophilic esophagitis, Behçet disease, endoscopic sclerotherapy for esophageal varices, and glutaraldehyde contamination at endoscopy. Esophageal strictures are best evaluated with biphasic esophagography that includes both single- and double-contrast spot images. When esophageal strictures are detected at barium examination, the underlying cause can often be determined with a pattern approach that takes into account the clinical history, the appearance and location of the strictures, and the presence of other associated radiographic findings., (Copyright RSNA, 2003)
- Published
- 2003
- Full Text
- View/download PDF
27. Pulmonary sarcoidosis: calcified micronodular pattern simulating pulmonary alveolar microlithiasis.
- Author
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Weinstein DS
- Subjects
- Adult, Biopsy, Bronchoscopy, Diagnosis, Differential, Disease Progression, Fatal Outcome, Female, Follow-Up Studies, Humans, Lithiasis complications, Radiography, Thoracic, Sarcoidosis, Pulmonary complications, Sarcoidosis, Pulmonary pathology, Lithiasis diagnosis, Pulmonary Alveoli diagnostic imaging, Pulmonary Alveoli pathology, Sarcoidosis, Pulmonary diagnostic imaging
- Abstract
A case of sarcoidosis demonstrating an unusual pattern of profuse micronodular calcification is presented. The striking similarity with the so-called pathognomonic appearance of pulmonary alveolar microlithiasis and the progressive deterioration of pulmonary function are emphasized.
- Published
- 1999
28. Enteral formulas.
- Author
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Weinstein DS and Furman J
- Subjects
- Humans, Enteral Nutrition nursing, Food, Formulated
- Abstract
This article is intended to assist the nurse in caring for the patient who requires medical nutritional formulas, either as a complete diet or as a dietary supplement, to increase the nurse's knowledge of formula components, when and why different formulas are used, and when a change in formula may be indicated. Common formulas are broadly categorized throughout the article based on the form of the protein.
- Published
- 1997
29. The chemical end-ligation of homopyrimidine oligodeoxyribonucleotides within a DNA triple helix.
- Author
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Li T, Weinstein DS, and Nicolaou K
- Subjects
- DNA Replication physiology, Indicators and Reagents, Nucleic Acid Conformation, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Templates, Genetic, DNA chemistry, Oligodeoxyribonucleotides chemistry
- Abstract
Background: Triple-helical nucleic acids, first reported in the late 1950s, are receiving attention for their possible involvement in controlling gene expression. Certain sequences of DNA are believed to form local triple-helical structures (H-form DNA), although this has not been directly observed in vivo. Studies carried out in our laboratories have suggested that self-replicating oligonucleotides could have been involved in chemical evolution via triple-helical intermediates. In addition to self-replication mechanisms, elucidating processes for the nonenzymatic elongation of biologically relevant polymers remains an important challenge in understanding the origin of life. To this end, we have studied a novel ligation of oligodeoxyribonucleotides that lie within a triple helix., Results: The chemical end-ligation of homopyrimidine oligodeoxyribonucleotides on a triple helix is reported. This selective process, induced by cyanoimidazole, is facilitated by a template effect of the DNA aggregate and occurs between the 3' end (hydroxyl) of the third minor-groove-bound strand and the 5' end (phosphate) of the antiparallel oligopyrimidine strand., Conclusions: Double-helical homopurine/homopyrimidine DNA can serve as a template for the elongation of oligonucleotides in a manner that has not been described previously. The end-ligation of homopyrimidine oligomers, a nonenzymatic process, proceeds via a requisite triple-helical intermediate and constitutes an efficient and selective method for the template-directed elongation of nucleic acids. Such a process could conceivably have been involved in the elongation of primordial information-bearing biopolymers.
- Published
- 1997
- Full Text
- View/download PDF
30. Lymphangiographic detection of scalene node metastases from cervical carcinoma.
- Author
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Steinfeld AD and Weinstein DS
- Subjects
- Adult, Carcinoma, Squamous Cell pathology, Female, Humans, Lymphatic Metastasis, Lymphography, Uterine Cervical Neoplasms pathology, Carcinoma, Squamous Cell diagnostic imaging, Uterine Cervical Neoplasms diagnostic imaging
- Published
- 1978
- Full Text
- View/download PDF
31. AN ATTEMPT TO REPLICATE A STUDY OF DISARRANGED EYE-HAND COORDINATION.
- Author
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WEINSTEIN S, SERSEN EA, and WEINSTEIN DS
- Subjects
- Humans, Adaptation, Ocular, Adaptation, Physiological, Eye, Hand, Motor Skills, Movement, Visual Perception
- Published
- 1964
- Full Text
- View/download PDF
32. The parathyroids in sudden, unexpected death in infants.
- Author
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Valdés-Dapena MA and Weinstein DS
- Subjects
- Autopsy, Calcium blood, Humans, Infant, Parathyroid Glands growth & development, Stress, Physiological physiopathology, Thymus Gland growth & development, Thymus Gland physiopathology, Death, Sudden, Parathyroid Glands pathology, Thymus Gland pathology
- Published
- 1971
- Full Text
- View/download PDF
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