David M Goldstein
Affiliation: F. Hoffmann-La Roche Ltd
- High-throughput kinase profiling as a platform for drug discoveryDavid M Goldstein
Roche Palo Alto, 3431 Hillview Avenue, R6 201, Palo Alto, California 94304, USA
Nat Rev Drug Discov 7:391-7. 2008..Compound potency and selectivity are determined simultaneously, providing a choice of targets to pursue that is guided by the quality of lead compounds available, rather than by target biology alone...
- Pathway to the clinic: inhibition of P38 MAP kinase. A review of ten chemotypes selected for developmentDavid M Goldstein
Department of Medicinal Chemistry, Roche Palo Alto, 3431 Hillview Ave, Palo Alto, CA 94304, USA
Curr Top Med Chem 5:1017-29. 2005..The pharmacology of the Roche compounds is then compared with eight chemically distinct p38 inhibitors known to have entered clinical development...
- Discovery of S-[5-amino-1-(4-fluorophenyl)-1H-pyrazol-4-yl]-[3-(2,3-dihydroxypropoxy)phenyl]methanone (RO3201195), an orally bioavailable and highly selective inhibitor of p38 MAP kinaseDavid M Goldstein
Roche Palo Alto LLC, 3431 Hillview Avenue, R6 123, Palo Alto, California 94304, USA
J Med Chem 49:1562-75. 2006..These efforts identified 63 (RO3201195) as an orally bioavailable and highly selective inhibitor of p38 which was selected for advancement into Phase I clinical trials...
- Discovery of 6-(2,4-difluorophenoxy)-2-[3-hydroxy-1-(2-hydroxyethyl)propylamino]-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (pamapimod) and 6-(2,4-difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (R1487) as orally David M Goldstein
Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, California 94304, United States
J Med Chem 54:2255-65. 2011..This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties...
- Design and synthesis of 4-azaindoles as inhibitors of p38 MAP kinaseAlejandra Trejo
Department of Medicinal Chemistry, Roche Palo Alto LLC, 3431 Hillview Avenue, R6 201, Palo Alto, California 94304, USA
J Med Chem 46:4702-13. 2003..These efforts identified 42c as a potent inhibitor of p38, which also possessed the required physical properties worthy of advanced studies...
- 3-Amino-pyrazolo[3,4-d]pyrimidines as p38α kinase inhibitors: design and development to a highly selective leadMichael Soth
Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304, USA
Bioorg Med Chem Lett 21:3452-6. 2011..Learnings from previous Roche p38-selective inhibitors were applied to a new fragment hit, which was optimized to a potent, exquisitely selective preclinical lead with a good pharmacokinetic profile...
- Pamapimod, a novel p38 mitogen-activated protein kinase inhibitor: preclinical analysis of efficacy and selectivityRonald J Hill
Department of Cellular and Molecular Pharmacology, Roche Pharmaceuticals, Palo Alto, CA 94304, USA
J Pharmacol Exp Ther 327:610-9. 2008..Our study demonstrates that pamapimod is a potent, selective inhibitor of p38alpha with the ability to inhibit the signs and symptoms of RA and other autoimmune diseases...
- Modeling bone marrow toxicity using kinase structural motifs and the inhibition profiles of small molecular kinase inhibitorsAndrew J Olaharski
Non Clinical Safety, Hoffmann La Roche, Nutley, New Jersey 07110, USA
Toxicol Sci 118:266-75. 2010..A support vector machine classifier was trained on the selected kinases and accurately predicts BMT with 74% accuracy. The model provides an efficient method for understanding SMKI-induced in vivo BMT earlier in drug discovery...
- Development of amino-pyrimidine inhibitors of c-Jun N-terminal kinase (JNK): kinase profiling guided optimization of a 1,2,3-benzotriazole leadWylie S Palmer
Roche Palo Alto, 3431 Hillview Ave, Palo Alto, CA 94304, USA
Bioorg Med Chem Lett 23:1486-92. 2013....