David M Goldstein
Affiliation: F. Hoffmann-La Roche Ltd
- 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...
- 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...
- 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...
- Structure-based drug design of RN486, a potent and selective Bruton's tyrosine kinase (BTK) inhibitor, for the treatment of rheumatoid arthritisYan Lou
pRED, Pharma Research and Early Development, Small Molecule Research, Discovery Chemistry, Hoffmann La Roche Inc, 3431 Hillview Avenue, Palo Alto, California 94304, United States
J Med Chem 58:512-6. 2015..Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J. Pharmacol. Exp. Ther. 2012 , 341 , 90 ), which was selected for advanced preclinical characterization based on its favorable 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...
- 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....
- 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...
- Finding the perfect spot for fluorine: improving potency up to 40-fold during a rational fluorine scan of a Bruton's Tyrosine Kinase (BTK) inhibitor scaffoldYan Lou
Hoffmann La Roche Inc, pRED, Pharma Research and Early Development, Small Molecule Research, Discovery Chemistry, 3431 Hillview Ave, Palo Alto, CA 94304, United States Electronic address
Bioorg Med Chem Lett 25:367-71. 2015..Comparison of co-crystal structures of parent molecules and fluorinated counterparts revealed the importance of placing fluorine at the optimal position to achieve favorable interactions with protein side chains. ..