Vertebrate Collagenase Inhibitor: II: 1) Tetrapeptidyl Hydroxamic Acids

Abstract

To develop a potent and specific collagenase inhibitor, a series of tetrapeptidyl hydroxamic acids were synthesized, based on the previous findings with tripeptidyl derivatives (Chem. Pharm. Bull., 38, 1007—1011, 1990). Among the series of tetrapeptidyl derivatives synthesized, R-Gly-Pro-Leu-Ala-NHOH and R-Gly-Pro-D-Leu-D-Ala-NHOH were found to be highly specific and potent inhibitors against vertebrate collagenase with an IC50 of 10-6 m order, where R stands for Boc or acyl group. Analysis of their structure-activity relationships showed a characteristic feature of the substrate-binding site of collagenase as follows: 1) the S1subsite forms a shallow hydrophobic pocket, although glycine residue corresponds to the subsite of the natural collagen substrate: 2) the S2 subsite constitutes a bulky pocket with less requirement for hydrophobicity: 3) the S3 subsite preferentially accommodates Pro residue: and 4) the accommodation of the P4-Pi subsites of peptidyl collagenase inhibitor to the S4-§1 subsites is required to form a tight binding of its hydroxamic acid moiety to the zinc ion at the catalytic site of the enzyme. The introduction of an enantiometric dipeptide unit, D-Leu-D-Ala, to the P2-Pi subsites demonstrated an increased binding capacity to the extended S4-Si subsites of collagenase, thus providing proteinase-resistant inhibitor. © 1991, The Pharmaceutical Society of Japan. All rights reserved.