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Bioorg Med Chem Lett. 2007 Feb 1;17(3):736-40. Epub 2006 Oct 28.

Benzothiazole benzimidazole (S)-isothiazolidinone derivatives as protein tyrosine phosphatase-1B inhibitors.

Author information

1
Incyte Corporation, Discovery Chemistry, Experimental Station, Route 141 and Henry Clay Road, Wilmington, DE 19880, USA. rsparks@incyte.com

Abstract

Benzothiazole benzimidazole (S)-isothiazolidinone ((S)-IZD) derivatives 5 were discovered through a peptidomimetic modification of the tripeptide (S)-IZD protein tyrosine phosphatase 1B (PTP1B) inhibitor 1. These derivatives are potent, competitive, and reversible inhibitors of PTP1B with improved caco-2 permeability. An X-ray co-crystal structure of inhibitor 5/PTP1B at 2.2A resolution demonstrated that the benzothiazole benzimidazole forms bi-dentate H-bonds to Asp48, and the benzothiazole interacts with the surface of the protein in a solvent exposed region towards the C-site. The design, synthesis, and SAR of this novel series of benzothiazole benzimidazole containing (S)-IZD inhibitors of PTP1B are presented herein.

PMID:
17097290
DOI:
10.1016/j.bmcl.2006.10.079
[Indexed for MEDLINE]

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