Discovery and design of benzimidazolone based inhibitors of p38 MAP kinase.
A new class of benzimidazolone p38 MAP kinase inhibitors was discovered through high-throughput screening. X-ray crystallographic data of the lead molecule with p38 were used to design analogues with improved binding affinity and potency in a cell assay of LPS-induced TNFalpha production. Herein, we report the SAR of this new class of p38 inhibitors.
Hammach
Abdelhakim
A
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA.
Barbosa
Antonio
A
Gaenzler
Faith Corbo
FC
Fadra
Tazmeen
T
Goldberg
Daniel
D
Hao
Ming-Hong
MH
Kroe
Rachel R
RR
Liu
Pingrong
P
Qian
Kevin C
KC
Ralph
Mark
M
Sarko
Christopher
C
Soleymanzadeh
Fariba
F
Moss
Neil
N
D001562:Benzimidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry*
D001562:Benzimidazoles; D004791:Enzyme Inhibitors; C031000:benzimidazole; D048051:p38 Mitogen-Activated Protein Kinases