title: Design of potent and selective 2-aminobenzimidazole-based p38alpha MAP kinase inhibitors with excellent in vivo efficacy.
abstract: We report the design and discovery of a 2-aminobenzimidazole-based series of potent and highly selective p38alphainhibitors. The lead compound 1 had low-nanomolar activity in both ATP competitive enzyme binding and inhibition of TNFalpha release in macrophages. Compound 18 showed excellent pharmacokinetics properties and oral activity in the rat collagen induced arthritis model compared with other p38 reference compounds. A SAR strategy to address CyP3A4 liability is also described.
authors.affiliation: Eli Lilly and Co., Lilly S.A., Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain. a.de_dios@lilly.com
authors.forename: Alfonso
authors.initials: A
authors.lastname: de Dios
authors.forename: Chuan
authors.initials: C
authors.lastname: Shih
authors.forename: Beatriz
authors.initials: B
authors.lastname: López de Uralde
authors.forename: Concepción
authors.initials: C
authors.lastname: Sánchez
authors.forename: Miriam
authors.initials: M
authors.lastname: del Prado
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Martín Cabrejas
authors.forename: Sehila
authors.initials: S
authors.lastname: Pleite
authors.forename: Jaime
authors.initials: J
authors.lastname: Blanco-Urgoiti
authors.forename: María José
authors.initials: MJ
authors.lastname: Lorite
authors.forename: C Richard
authors.initials: CR
authors.lastname: Nevill
authors.forename: Rosanne
authors.initials: R
authors.lastname: Bonjouklian
authors.forename: Jeremy
authors.initials: J
authors.lastname: York
authors.forename: Michal
authors.initials: M
authors.lastname: Vieth
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Nicholas
authors.initials: N
authors.lastname: Magnus
authors.forename: Robert M
authors.initials: RM
authors.lastname: Campbell
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Anderson
authors.forename: Denis J
authors.initials: DJ
authors.lastname: McCann
authors.forename: Deborah D
authors.initials: DD
authors.lastname: Giera
authors.forename: Paul A
authors.initials: PA
authors.lastname: Lee
authors.forename: Richard M
authors.initials: RM
authors.lastname: Schultz
authors.forename: Li C
authors.initials: LC
authors.lastname: Li
authors.forename: Lea M
authors.initials: LM
authors.lastname: Johnson
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Wolos
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001682:Biological Availability; D003094:Collagen; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D000893:Anti-Inflammatory Agents; D001562:Benzimidazoles; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D048308:Mitogen-Activated Protein Kinase 14