Rational Design and Combinatorial Evaluation of Enzyme Inhibitor Scaffolds:  Identification of Novel Inhibitors of Matrix Metalloproteinases

• Published in: Journal of medicinal chemistry 1998-06, Vol.41 (13), p.2194-2200
• Main Authors: Szardenings, Anna Katrin, Harris, David, Lam, Stuart, Shi, Lihong, Tien, David, Wang, Yongwen, Patel, Dinesh V, Navre, Marc, Campbell, David A
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Diketopiperazines; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Hydrogen Bonding; Matrix Metalloproteinase 1; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Medical sciences; Metalloendopeptidases - antagonists & inhibitors; Miscellaneous; Pharmacology. Drug treatments; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980133j

The discovery of a novel series of heterocyclic matrix metalloproteinase (MMPs) inhibitors is described. Published crystal structures of peptidyl hydroxamates bound to MMPs were the basis for the rational design of diketopiperazine (DKP) inhibitors. Combinatorial libraries were prepared and evaluated for their ability to inhibit collagenase-1, stromelysin-1, and gelatinase-B substrate hydrolysis. Deconvolution of active pools resulted in the identification of potent inhibitors (IC50's < 100 nM) of collagenase-1 and gelatinase-B, with the most potent inhibitor exhibiting an IC50 of 30 nM against collagenase-1. A description of the combinatorial evaluation process, as well as initial SAR interpretation for this novel series, is provided.