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

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