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J Med Chem. 2002 Nov 7;45(23):4954-7.

Discovery of gamma-lactam hydroxamic acids as selective inhibitors of tumor necrosis factor alpha converting enzyme: design, synthesis, and structure-activity relationships.

Author information

1
Discovery Chemistry, Bristol-Myers Squibb Company, Experimental Station, Wilmington, Delaware 19880-0500, USA. james.duan@bms.com

Abstract

New gamma-lactam TACE inhibitors were designed from known MMP inhibitors. A homology model of TACE was built and examined to identify the S1' site as the key area for TACE selectivity over MMPs. Rational exploration of the P1'-S1' interactions resulted in the discovery of the 3,5-disubstituted benzyl ether as a TACE-selective P1' group. Further optimization led to the discovery of IK682 as a selective and orally bioavailable TACE inhibitor.

PMID:
12408705
DOI:
10.1021/jm0255670
[Indexed for MEDLINE]

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