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
  • 1. Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, California 94304, United States. [email protected]
PMID: 21375264 DOI: 10.1021/jm101423y
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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