2. Academic Validation
  3. 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

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

Affiliation

  • 1 Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, California 94304, United States. David-M.Goldstein@roche.com
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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