Hit to lead account of the discovery of bisbenzamide and related ureidobenzamide inhibitors of Rho kinase.
A highly selective series of bisbenzamide inhibitors of Rho-associated coiled-coil forming protein kinase (ROCK) and a related ureidobenzamide series, both identified by high throughput screening (HTS), are described. Details of the hit validation and lead generation process, including structure-activity relationship (SAR) studies, a selectivity assessment, target-independent profiling (TIP) results, and an analysis of functional activity using a rat aortic ring assay are discussed.
Morwick
Tina
T
Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06801-0368, USA. tmorwick@rdg.boehringer-ingelheim.com
Büttner
Frank H
FH
Cywin
Charles L
CL
Dahmann
Georg
G
Hickey
Eugene
E
Jakes
Scott
S
Kaplita
Paul
P
Kashem
Mohammed A
MA
Kerr
Steven
S
Kugler
Stanley
S
Mao
Wang
W
Marshall
Daniel
D
Paw
Zofia
Z
Shih
Cheng-Kon
CK
Wu
Frank
F
Young
Erick
E
D000818:Animals; D001011:Aorta / Q000201:enzymology; D006690:Bisbenzimidazole / Q000737:chemistry* / Q000494:pharmacology; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical / Q000379:methods; D020128:Inhibitory Concentration 50; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
D047428:Protein Kinase Inhibitors; D014508:Urea; D054460:rho-Associated Kinases; D006690:Bisbenzimidazole