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 PMID: 21375264

ADC Targets in Oncology

2026-04-10

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

J Med Chem. 2011 Apr 14;54(7):2255-65. doi: 10.1021/jm101423y.

David M Goldstein ¹ , Michael Soth , Tobias Gabriel , Nolan Dewdney , Andreas Kuglstatter , Humberto Arzeno , Jeffrey Chen , William Bingenheimer , Stacie A Dalrymple , James Dunn , Robert Farrell , Sandra Frauchiger , JoAnn La Fargue , Manjiri Ghate , Bradford Graves , Ronald J Hill , Fujun Li , Renee Litman , Brad Loe , Joel McIntosh , Daniel McWeeney , Eva Papp , Jaehyeon Park , Harlan F Reese , Richard T Roberts , David Rotstein , Bong San Pablo , Keshab Sarma , Martin Stahl , Man-Ling Sung , Rebecca T Suttman , Eric B Sjogren , Yunchou Tan , Alejandra Trejo , Mary Welch , Paul Weller , Brian R Wong , Hasim Zecic

Affiliations

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.