title: The discovery of N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (AZD6703), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases.
abstract: A novel, potent and selective quinazolinone series of inhibitors of p38α MAP kinase has been identified. Modifications designed to address the issues of poor aqueous solubility and high plasma protein binding as well as embedded aniline functionalities resulted in the identification of a clinical candidate N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (AZD6703). Optimisation was guided by understanding of the binding modes from X-ray crystallographic studies which showed a switch from DFG 'out' to DFG 'in' as the inhibitor size was reduced to improve overall properties.
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Dearg S
authors.initials: DS
authors.lastname: Brown
authors.forename: John G
authors.initials: JG
authors.lastname: Cumming
authors.forename: Paul
authors.initials: P
authors.lastname: Bethel
authors.forename: Jonathan
authors.initials: J
authors.lastname: Finlayson
authors.forename: Stefan
authors.initials: S
authors.lastname: Gerhardt
authors.forename: Ian
authors.initials: I
authors.lastname: Nash
authors.forename: Richard A
authors.initials: RA
authors.lastname: Pauptit
authors.forename: Kurt G
authors.initials: KG
authors.lastname: Pike
authors.forename: Alan
authors.initials: A
authors.lastname: Reid
authors.forename: Wendy
authors.initials: W
authors.lastname: Snelson
authors.forename: Steve
authors.initials: S
authors.lastname: Swallow
authors.forename: Caroline
authors.initials: C
authors.lastname: Thompson
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001798:Blood Proteins / Q000737:chemistry; D018360:Crystallography, X-Ray; D004285:Dogs; D055808:Drug Discovery; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D008970:Molecular Weight; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001798:Blood Proteins; C575094:N-(3,4-dichlorophenyl)-4-((2R)-4-isopropylpiperazine-2-carbonyl)piperazine-1-carboxamide; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D048308:Mitogen-Activated Protein Kinase 14