Document Report Card

ID: ALA1134694

Journal: J Med Chem

Title: Discovery of macrocyclic hydroxamic acids containing biphenylmethyl derivatives at P1', a series of selective TNF-alpha converting enzyme inhibitors with potent cellular activity in the inhibition of TNF-alpha release.

Authors: Xue CB, He X, Corbett RL, Roderick J, Wasserman ZR, Liu RQ, Jaffee BD, Covington MB, Qian M, Trzaskos JM, Newton RC, Magolda RL, Wexler RR, Decicco CP.

Abstract: SAR exploration at P1' using an anti-succinate-based macrocyclic hydroxamic acid as a template led to the identification of several bulky biphenylmethyl P1' derivatives which confer potent porcine TACE and anti-TNF-alpha cellular activities with high selectivity versus most of the MMPs screened. Our studies demonstrate for the first time that TACE has a larger S1' pocket in comparison to MMPs and that potent and selective TACE inhibitors can be achieved by incorporation of sterically bulky P1' residues.

CiteXplore: 11585440

DOI: 10.1021/jm0155502