title: Hit to lead account of the discovery of bisbenzamide and related ureidobenzamide inhibitors of Rho kinase.
abstract: 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.
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06801-0368, USA. tmorwick@rdg.boehringer-ingelheim.com
authors.forename: Tina
authors.initials: T
authors.lastname: Morwick
authors.forename: Frank H
authors.initials: FH
authors.lastname: Büttner
authors.forename: Charles L
authors.initials: CL
authors.lastname: Cywin
authors.forename: Georg
authors.initials: G
authors.lastname: Dahmann
authors.forename: Eugene
authors.initials: E
authors.lastname: Hickey
authors.forename: Scott
authors.initials: S
authors.lastname: Jakes
authors.forename: Paul
authors.initials: P
authors.lastname: Kaplita
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Kashem
authors.forename: Steven
authors.initials: S
authors.lastname: Kerr
authors.forename: Stanley
authors.initials: S
authors.lastname: Kugler
authors.forename: Wang
authors.initials: W
authors.lastname: Mao
authors.forename: Daniel
authors.initials: D
authors.lastname: Marshall
authors.forename: Zofia
authors.initials: Z
authors.lastname: Paw
authors.forename: Cheng-Kon
authors.initials: CK
authors.lastname: Shih
authors.forename: Frank
authors.initials: F
authors.lastname: Wu
authors.forename: Erick
authors.initials: E
authors.lastname: Young
mesh_terms: 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*
chemical_list: D047428:Protein Kinase Inhibitors; D014508:Urea; D054460:rho-Associated Kinases; D006690:Bisbenzimidazole