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Bioorg Med Chem Lett. 2011 Jan 1;21(1):97-101. doi: 10.1016/j.bmcl.2010.11.060. Epub 2010 Nov 19.

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

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Discovery Research, MSD, Newhouse, Lanarkshire ML1 5SH, Scotland, UK.


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.

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