p38alpha mitogen-activated protein kinase inhibitors: optimization of a series of biphenylamides to give a molecule suitable for clinical progression.
p38alpha MAP kinase is a key anti-inflammatory target for rheumatoid arthritis, influencing biosynthesis of pro-inflammatory cytokines TNFalpha and IL-1beta at a translational and transcriptional level. In this paper, we describe how we have optimized a series of novel p38alpha/beta inhibitors using crystal structures of our inhibitors bound to p38alpha, classical medicinal chemistry, and modeling of virtual libraries to derive a molecule suitable for progression into clinical development.
Aston
Nicola M
NM
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Rd, Stevenage, Hertfordshire SG1 2NY, UK.
Bamborough
Paul
P
Buckton
Jacqueline B
JB
Edwards
Christopher D
CD
Holmes
Duncan S
DS
Jones
Katherine L
KL
Patel
Vipulkumar K
VK
Smee
Penny A
PA
Somers
Donald O
DO
Vitulli
Giovanni
G
Walker
Ann L
AL
D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy; D001713:Biphenyl Compounds / Q000737:chemistry*; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats
D000577:Amides; D001713:Biphenyl Compounds; D048308:Mitogen-Activated Protein Kinase 14; D047428:Protein Kinase Inhibitors; C010574:biphenyl