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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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Ray P,Wright J,Adam J,Bennett J,Boucharens S,Black D,Cook A,Brown AR,Epemolu O,Fletcher D,Haunso A,Huggett M,Jones P,Laats S,Lyons A,Mestres J,de Man J,Morphy R,Rankovic Z,Sherborne B,Sherry L,van Straten N,We

doi

10.1016/j.bmcl.2010.11.060

subject

Has Abstract

pub_date

2011-01-01 00:00:00

pages

97-101

issue

1

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(10)01685-9

journal_volume

21

pub_type

杂志文章

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