Document Report Card

ID: ALA1135609

Journal: J Med Chem

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

Authors: Duan JJ, Chen L, Wasserman ZR, Lu Z, Liu RQ, Covington MB, Qian M, Hardman KD, Magolda RL, Newton RC, Christ DD, Wexler RR, Decicco CP.

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.

CiteXplore: 12408705

DOI: 10.1021/jm0255670