Fragment-based discovery of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors期刊界 All Journals 搜尽天下杂志传播学术成果专业期刊搜索期刊信息化学术搜索

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Fragment-based discovery of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors

Authors:	Ray Peter Wright Jane Adam Julia Bennett Johnathan Boucharens Sylviane Black Darcey Cook Andrew Brown Angus R Epemolu Ola Fletcher Dan Haunso Anders Huggett Margaret Jones Phil Laats Steven Lyons Amanda Mestres Jordi de Man Jos Morphy Richard Rankovic Zoran Sherborne Brad Sherry Lorcan van Straten Nicole Westwood Paul Zaman Guido Z R

Institution:	Discovery Research, MSD, Newhouse, Lanarkshire ML1 5SH, Scotland, UK

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.

Keywords:	Rho kinase ROCK-I ROCK inhibitors Fragment-based drug discovery FBDD STD NMR
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