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Bioorg Med Chem Lett. 2007 Nov 15;17(22):6280-5. Epub 2007 Sep 7.

Synthesis and evaluation of substituted benzoisoquinolinones as potent inhibitors of Chk1 kinase.

Author information

1
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. robert_garbaccio@merck.com

Abstract

From HTS lead 1, a novel benzoisoquinolinone class of ATP-competitive Chk1 inhibitors was devised and synthesized via a photochemical route. Using X-ray crystallography as a guide, potency was rapidly enhanced through the installation of a tethered basic amine designed to interact with an acidic residue (Glu91) in the enzyme pocket. Further SAR was explored at the solvent front and near to the H1 pocket and resulted in the discovery of low MW, sub-nanomolar inhibitors of Chk1.

PMID:
17900896
DOI:
10.1016/j.bmcl.2007.09.007
[Indexed for MEDLINE]

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