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

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.