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-2

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• 作者：David M. Goldstein ; 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：April 14, 2011
• 年：2011
• 卷：54
• 期：7
• 页码：2255-2265
• 全文大小：1128K
• 年卷期：v.54,no.7(April 14, 2011)
• ISSN：1520-4804

文摘

The development of a new series of p38伪 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 p38伪, 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.