title: Fragment-based discovery of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors.
abstract: Fragment-based NMR screening of a small literature focused library led to identification of a historical thrombin/FactorXa building block, 17A, that was found to be a ROCK-I inhibitor. In the absence of an X-ray structure, fragment growth afforded 6-substituted isoquinolin-1-amine derivatives which were profiled in the primary ROCK-I IMAP assay. Compounds 23A and 23E were selected as fragment optimized hits for further profiling. Compound 23A has similar ROCK-1 affinity, potency and cell based efficacy to the first generation ROCK inhibitors, however, it has a superior PK profile in C57 mouse. Compound 23E demonstrates the feasibility of improving ROCK-1 affinity, potency and cell based efficacy for the series, however, it has a poor PK profile relative to 23A.
authors.affiliation: Discovery Research, MSD, Newhouse, Lanarkshire ML1 5SH, Scotland, UK. peter.ray@merck.com
authors.forename: Peter
authors.initials: P
authors.lastname: Ray
authors.forename: Jane
authors.initials: J
authors.lastname: Wright
authors.forename: Julia
authors.initials: J
authors.lastname: Adam
authors.forename: Johnathan
authors.initials: J
authors.lastname: Bennett
authors.forename: Sylviane
authors.initials: S
authors.lastname: Boucharens
authors.forename: Darcey
authors.initials: D
authors.lastname: Black
authors.forename: Andrew
authors.initials: A
authors.lastname: Cook
authors.forename: Angus R
authors.initials: AR
authors.lastname: Brown
authors.forename: Ola
authors.initials: O
authors.lastname: Epemolu
authors.forename: Dan
authors.initials: D
authors.lastname: Fletcher
authors.forename: Anders
authors.initials: A
authors.lastname: Haunso
authors.forename: Margaret
authors.initials: M
authors.lastname: Huggett
authors.forename: Phil
authors.initials: P
authors.lastname: Jones
authors.forename: Steven
authors.initials: S
authors.lastname: Laats
authors.forename: Amanda
authors.initials: A
authors.lastname: Lyons
authors.forename: Jordi
authors.initials: J
authors.lastname: Mestres
authors.forename: Jos
authors.initials: J
authors.lastname: de Man
authors.forename: Richard
authors.initials: R
authors.lastname: Morphy
authors.forename: Zoran
authors.initials: Z
authors.lastname: Rankovic
authors.forename: Brad
authors.initials: B
authors.lastname: Sherborne
authors.forename: Lorcan
authors.initials: L
authors.lastname: Sherry
authors.forename: Nicole
authors.initials: N
authors.lastname: van Straten
authors.forename: Paul
authors.initials: P
authors.lastname: Westwood
authors.forename: Guido Z R
authors.initials: GZ
authors.lastname: Zaman
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000588:Amines; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D054460:rho-Associated Kinases