p38α Mitogen-activated protein kinase inhibitors: optimization of a series of biphenylamides to give a molecule suitable for clinical progression

…, JB Buckton, CD Edwards, DS Holmes, KL Jones…

Index: Aston, Nicola M.; Bamborough, Paul; Buckton, Jacqueline B.; Edwards, Christopher D.; Holmes, Duncan S.; Jones, Katherine L.; Patel, Vipulkumar K.; Smee, Penny A.; Somers, Donald O.; Vitulli, Giovanni; Walker, Ann L. Journal of Medicinal Chemistry, 2009 , vol. 52, # 20 p. 6257 - 6269

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Citation Number: 29

Abstract

p38R MAP kinase is a key anti-inflammatory target for rheumatoid arthritis, influencing biosynthesis of pro-inflammatory cytokines TNFR and IL-1β at a translational and transcriptional level. In this paper, we describe how we have optimized a series of novel p38R/β inhibitors using crystal structures of our inhibitors bound to p38R, classical medicinal chemistry, and modeling of virtual libraries to derive a molecule suitable for progression ...