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Your search keyword '"Edwin J. Iwanowicz"' showing total 7 results
Start Over Author "Edwin J. Iwanowicz" Journal journal of medicinal chemistry
7 results on '"Edwin J. Iwanowicz"'

1. Acridone-Based Inhibitors of Inosine 5‘-Monophosphate Dehydrogenase: Discovery and SAR Leading to the Identification of N-(2-(6-(4-Ethylpiperazin-1-yl)pyridin-3-yl)propan-2-yl)-2- fluoro-9-oxo-9,10-dihydroacridine-3-carboxamide (BMS-566419)

Author

Sam T. Chao, Yufen Zhao, Katherine A. Rouleau, Zheng Yang, Henry H. Gu, Catherine A. Fleener, Zhongqi Shen, Jeffrey A. Robl, Kim W. McIntyre, Edwin J. Iwanowicz, Mark R. Witmer, Scott H. Watterson, Arvind Mathur, Bang-Chi Chen, Mary T. Obermeier, and Robert Townsend, Donna M. Dambach, T. G. Murali Dhar, Zili Xiao, Joel C. Barrish, Shelley K. Ballentine, David J. Shuster, and Ping Chen

Subjects
Male, Administration, Oral, Biological Availability, Guanosine, Pharmacology, Mycophenolate, Piperazines, Mycophenolic acid, Cell Line, Arthritis, Rheumatoid, Structure-Activity Relationship, chemistry.chemical_compound, IMP Dehydrogenase, IMP dehydrogenase, Drug Discovery, medicine, Animals, Humans, Inosine-5′-monophosphate dehydrogenase, Cell Proliferation, biology, Stereoisomerism, Prodrug, Arthritis, Experimental, Rats, Gastrointestinal Tract, Acridone, Macaca fascicularis, chemistry, Biochemistry, Rats, Inbred Lew, Enzyme inhibitor, Leukocytes, Mononuclear, biology.protein, Acridines, Molecular Medicine, Half-Life, medicine.drug
Abstract

Inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo synthesis of guanosine nucleotides, catalyzes the irreversible nicotinamide-adenine dinucleotide dependent oxidation of inosine-5'-monophosphate to xanthosine-5'-monophosphate. Mycophenolate Mofetil (MMF), a prodrug of mycophenolic acid, has clinical utility for the treatment of transplant rejection based on its inhibition of IMPDH. The overall clinical benefit of MMF is limited by what is generally believed to be compound-based, dose-limiting gastrointestinal (GI) toxicity that is related to its specific pharmacokinetic characteristics. Thus, development of an IMPDH inhibitor with a novel structure and a different pharmacokinetic profile may reduce the likelihood of GI toxicity and allow for increased efficacy. This article will detail the discovery and SAR leading to a novel and potent acridone-based IMPDH inhibitor 4m and its efficacy and GI tolerability when administered orally in a rat adjuvant arthritis model.

Published
2007
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2. Imidazoquinoxaline Src-Family Kinase p56Lck Inhibitors: SAR, QSAR, and the Discovery of (S)-N-(2-Chloro-6-methylphenyl)-2-(3-methyl-1-piperazinyl)imidazo- [1,5-a]pyrido[3,2-e]pyrazin-6-amine (BMS-279700) as a Potent and Orally Active Inhibitor with Excellent in Vivo Antiinflammatory Activity

Author

Steven H. Spergel, Robert V. Moquin, Ding Ren Shen, Jagabundhu Das, Gary L. Schieven, Kamelia Behnia, James Lin, O. Kocy, Paul L. Stanley, Sydney Pitt, John Wityak, Ping Chen, Sara Thrall, David J. Shuster, Derek J. Norris, Suhong Pang, Edwin J. Iwanowicz, Steven B. Kanner, Henry F. De Fex, Joel C. Barrish, Henry H. Gu, Kim W. McIntyre, Mark R. Witmer, Saeho Chong, and Arthur M. Doweyko

Subjects
chemistry.chemical_classification, Quantitative structure–activity relationship, Molecular model, Chemistry, In vivo, Stereochemistry, Drug Discovery, Molecular Medicine, Aromatic amine, Src family kinase, Chemical synthesis, In vitro, Proinflammatory cytokine
Abstract

A series of novel anilino 5-azaimidazoquinoxaline analogues possessing potent in vitro activity against p56Lck and T cell proliferation have been discovered. Subsequent SAR studies led to the identification of compound 4 (BMS-279700) as an orally active lead candidate that blocks the production of proinflammatory cytokines (IL-2 and TNFalpha) in vivo. In addition, an expanded set of imidazoquinoxalines provided several descriptive QSAR models highlighting the influence of significant steric and electronic features. The H-bonding (Met319) contribution to observed binding affinities within a tightly congeneric series was found to be significant.

Published
2004
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3. Discovery of N-[2-[2-[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]-5-oxazolyl]phenyl]-N-methyl-4- morpholineacetamide as a Novel and Potent Inhibitor of Inosine Monophosphate Dehydrogenase with Excellent in Vivo Activity

Author

T G Murali, Dhar, Zhongqi, Shen, Junqing, Guo, Chunjian, Liu, Scott H, Watterson, Henry H, Gu, William J, Pitts, Catherine A, Fleener, Katherine A, Rouleau, N Z, Sherbina, Kim W, McIntyre, David J, Shuster, Mark R, Witmer, Jeffrey A, Tredup, Bang-Chi, Chen, Rulin, Zhao, Mark S, Bednarz, Daniel L, Cheney, John F, MacMaster, Laura M, Miller, Karen K, Berry, Timothy W, Harper, Joel C, Barrish, Diane L, Hollenbaugh, and Edwin J, Iwanowicz

Subjects
Male, Purine, Stereochemistry, Morpholines, Enzyme-Linked Immunosorbent Assay, Chemical synthesis, Mice, Structure-Activity Relationship, chemistry.chemical_compound, IMP Dehydrogenase, In vivo, IMP dehydrogenase, Drug Discovery, Animals, Structure–activity relationship, Nucleotide, Enzyme Inhibitors, Oxazoles, chemistry.chemical_classification, Mice, Inbred BALB C, biology, Mycophenolic Acid, Arthritis, Experimental, Rats, De novo synthesis, Biochemistry, chemistry, Rats, Inbred Lew, Enzyme inhibitor, Antibody Formation, biology.protein, Molecular Medicine
Abstract

Inosine monophosphate dehydrogenase (IMPDH) is a key enzyme that is involved in the de novo synthesis of purine nucleotides. Novel 2-aminooxazoles were synthesized and tested for inhibition of IMPDH catalytic activity. Multiple analogues based on this chemotype were found to inhibit IMPDH with low nanomolar potency. One of the analogues (compound 23) showed excellent in vivo activity in the inhibition of antibody production in mice and in the adjuvant induced arthritis model in rats.

Published
2002
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4. Discovery and development of 5-[(5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl-methyl]-3-thiophenecarboxylic acid (BMS-587101)--a small molecule antagonist of leukocyte function associated antigen-1

Author

Dominique, Potin, Michele, Launay, Francoise, Monatlik, Patrice, Malabre, Maud, Fabreguettes, Andre, Fouquet, Magali, Maillet, Eric, Nicolai, Loïc, Dorgeret, François, Chevallier, Dominique, Besse, Monique, Dufort, François, Caussade, Syed Z, Ahmad, Dawn K, Stetsko, Stacey, Skala, Patricia M, Davis, Praveen, Balimane, Karishma, Patel, Zheng, Yang, Punit, Marathe, Jennifer, Postelneck, Robert M, Townsend, Valentina, Goldfarb, Steven, Sheriff, Howard, Einspahr, Kevin, Kish, Mary F, Malley, John D, DiMarco, Jack Z, Gougoutas, Pathanjali, Kadiyala, Daniel L, Cheney, Ravindra W, Tejwani, Denette K, Murphy, Kim W, Mcintyre, Xiaoxia, Yang, Sam, Chao, Leslie, Leith, Zili, Xiao, Arvind, Mathur, Bang-Chi, Chen, Daugh-Rurng, Wu, Sarah C, Traeger, Murray, McKinnon, Joel C, Barrish, Jeffrey A, Robl, Edwin J, Iwanowicz, Suzanne J, Suchard, and T G Murali, Dhar

Subjects
Graft Rejection, Models, Molecular, Molecular Structure, Stereoisomerism, Pneumonia, Thiophenes, Crystallography, X-Ray, Lymphocyte Function-Associated Antigen-1, Mice, Structure-Activity Relationship, Dogs, Cell Adhesion, Animals, Humans, Transplantation, Homologous, Spiro Compounds
Abstract

LFA-1 (leukocyte function-associated antigen-1), is a member of the beta2-integrin family and is expressed on all leukocytes. This letter describes the discovery and preliminary SAR of spirocyclic hydantoin based LFA-1 antagonists that culminated in the identification of analog 8 as a clinical candidate. We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection.

Published
2006

5. Imidazoquinoxaline Src-family kinase p56Lck inhibitors: SAR, QSAR, and the discovery of (S)-N-(2-chloro-6-methylphenyl)-2-(3-methyl-1-piperazinyl)imidazo- [1,5-a]pyrido[3,2-e]pyrazin-6-amine (BMS-279700) as a potent and orally active inhibitor with excellent in vivo antiinflammatory activity

Author

Ping, Chen, Arthur M, Doweyko, Derek, Norris, Henry H, Gu, Steven H, Spergel, Jagabundhu, Das, Robert V, Moquin, James, Lin, John, Wityak, Edwin J, Iwanowicz, Kim W, McIntyre, David J, Shuster, Kamelia, Behnia, Saeho, Chong, Henry, de Fex, Suhong, Pang, Sydney, Pitt, Ding Ren, Shen, Sara, Thrall, Paul, Stanley, Octavian R, Kocy, Mark R, Witmer, Steven B, Kanner, Gary L, Schieven, and Joel C, Barrish

Subjects
Models, Molecular, Anti-Inflammatory Agents, Biological Availability, Quantitative Structure-Activity Relationship, Hydrogen Bonding, Mice, Inbred C57BL, Inhibitory Concentration 50, Mice, src-Family Kinases, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Pyrazines, Quinoxalines, Animals, Cytokines, Female, Enzyme Inhibitors
Abstract

A series of novel anilino 5-azaimidazoquinoxaline analogues possessing potent in vitro activity against p56Lck and T cell proliferation have been discovered. Subsequent SAR studies led to the identification of compound 4 (BMS-279700) as an orally active lead candidate that blocks the production of proinflammatory cytokines (IL-2 and TNFalpha) in vivo. In addition, an expanded set of imidazoquinoxalines provided several descriptive QSAR models highlighting the influence of significant steric and electronic features. The H-bonding (Met319) contribution to observed binding affinities within a tightly congeneric series was found to be significant.

Published
2004

6. Retro-binding tripeptide thrombin active-site inhibitors: discovery, synthesis, and molecular modeling

Author

Edwin J. Iwanowicz, Wan F. Lau, James Lin, Steven M. Seiler, and Daniel G.M. Roberts

Subjects
Models, Molecular, Serine Proteinase Inhibitors, Molecular model, Stereochemistry, Molecular Sequence Data, Tripeptide, Chemical synthesis, Structure-Activity Relationship, Thrombin, Drug Discovery, medicine, Amino Acid Sequence, Binding site, chemistry.chemical_classification, Binding Sites, biology, Active site, Enzyme, Biochemistry, chemistry, Enzyme inhibitor, biology.protein, Molecular Medicine, Oligopeptides, medicine.drug
Published
1994

7. Discovery of N-[2-[2-[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]-5-oxazolyl]phenyl]-N-methyl-4-morpholineacetamide as a Novel and Potent Inhibitor of Inosine Monophosphate Dehydrogenase (IMPDH) with Excellent in Vivo Activity

Author

T. G. Murali Dhar, Zhongqi Shen, Junqing Guo, Chunjian Liu, Scott H. Watterson, Henry H. Gu, William J. Pitts, Catherine A. Fleener, Katherine A. Rouleau, N. Z. Sherbina, Kim W. McIntyre, David J. Shuster, Mark R. Witmer, Jeffrey A. Tredup, Bang-Chi Chen, Rulin Zhao, Mark S. Bednarz, Daniel L. Cheney, John F. MacMaster, Laura M. Miller, Karen K. Berry, Timothy W. Harper, Joel C. Barrish, Diane L. Hollenbaugh, and Edwin J. Iwanowicz

Subjects
Drug Discovery, Molecular Medicine
Published
2002
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