Design of potent and selective 2-aminobenzimidazole-based p38alpha MAP kinase inhibitors with excellent in vivo efficacy.
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.
de Dios
Alfonso
A
Eli Lilly and Co., Lilly S.A., Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain. a.de_dios@lilly.com
Shih
Chuan
C
López de Uralde
Beatriz
B
Sánchez
Concepción
C
del Prado
Miriam
M
Martín Cabrejas
Luisa M
LM
Pleite
Sehila
S
Blanco-Urgoiti
Jaime
J
Lorite
María José
MJ
Nevill
C Richard
CR
Bonjouklian
Rosanne
R
York
Jeremy
J
Vieth
Michal
M
Wang
Yong
Y
Magnus
Nicholas
N
Campbell
Robert M
RM
Anderson
Bryan D
BD
McCann
Denis J
DJ
Giera
Deborah D
DD
Lee
Paul A
PA
Schultz
Richard M
RM
Li
Li C
LC
Johnson
Lea M
LM
Wolos
Jeffrey A
JA
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
D000893:Anti-Inflammatory Agents; D001562:Benzimidazoles; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D048308:Mitogen-Activated Protein Kinase 14