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 Bioavailable and Highly Selective Inhibitors of p38α Mitogen-Activated Protein Kinase
Journal of Medicinal Chemistry2011Vol. 54(7), pp. 2255–2265
Citations Over TimeTop 21% of 2011 papers
David Goldstein, Michael Soth, Tobias Gabriel, Nolan Dewdney, A. Kuglstatter, Humberto Arzeno, Jeffrey Chen, W. BINGENHEIMER, Stacie A. Dalrymple, James P. Dunn, Robert Farrell, Sandra Frauchiger, JoAnn La Fargue, M. Ghate, Bradford Graves, Ronald J. Hill, Fujun Li, Renée Litman, Brad Loe, Joel McIntosh, Daniel McWeeney, Eva Papp, Jae Hyeon Park, Harlan F. Reese, Richard T. Roberts, David S. Rotstein, Bong San Pablo, Keshab Sarma, Martin Ståhl, Man-Ling Sung, Rebecca Suttman, Eric B. Sjogren, Yun-Chou Tan, Alejandra Trejo, Mary Welch, Paul Weller, Brian Wong, Hasim Zecic
Abstract
The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.
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