title: p38alpha mitogen-activated protein kinase inhibitors: optimization of a series of biphenylamides to give a molecule suitable for clinical progression.
abstract: 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.
authors.affiliation: GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Rd, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: Nicola M
authors.initials: NM
authors.lastname: Aston
authors.forename: Paul
authors.initials: P
authors.lastname: Bamborough
authors.forename: Jacqueline B
authors.initials: JB
authors.lastname: Buckton
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Edwards
authors.forename: Duncan S
authors.initials: DS
authors.lastname: Holmes
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Jones
authors.forename: Vipulkumar K
authors.initials: VK
authors.lastname: Patel
authors.forename: Penny A
authors.initials: PA
authors.lastname: Smee
authors.forename: Donald O
authors.initials: DO
authors.lastname: Somers
authors.forename: Giovanni
authors.initials: G
authors.lastname: Vitulli
authors.forename: Ann L
authors.initials: AL
authors.lastname: Walker
mesh_terms: 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
chemical_list: D000577:Amides; D001713:Biphenyl Compounds; D048308:Mitogen-Activated Protein Kinase 14; D047428:Protein Kinase Inhibitors; C010574:biphenyl