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

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

Bioorganic & medicinal chemistry letters (2010-12-15)
Peter Ray, Jane Wright, Julia Adam, Johnathan Bennett, Sylviane Boucharens, Darcey Black, Andrew Cook, Angus R Brown, Ola Epemolu, Dan Fletcher, Anders Haunso, Margaret Huggett, Phil Jones, Steven Laats, Amanda Lyons, Jordi Mestres, Jos de Man, Richard Morphy, Zoran Rankovic, Brad Sherborne, Lorcan Sherry, Nicole van Straten, Paul Westwood, Guido Z R Zaman
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.

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Acetophenone, ReagentPlus®, 99%
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Salicylamide, 99%
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Acetophenone, puriss. p.a., ≥99.0% (GC)
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Acetophenone, analytical standard
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Isoquinoline, 97%
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Acetophenone, ≥98%, FG
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Benzimidazole, 98%
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