Document Report Card

ID: ALA1132120

Journal: J Med Chem

Title: Identification of highly selective inhibitors of collagenase-1 from combinatorial libraries of diketopiperazines.

Authors: Szardenings AK, Antonenko V, Campbell DA, DeFrancisco N, Ida S, Shi L, Sharkov N, Tien D, Wang Y, Navre M.

Abstract: Thiol-containing diketopiperazines have been recently identified as novel heterocyclic inhibitors of matrix metalloproteinase (MMPs). The compounds described had similar activities against the MMPs collagenase-1 and gelatinase-B. An inhibitor that showed greater than 10-fold selectivity for collagenase-1 over gelatinase-B was desired. Previously published work with peptidyl hydroxamates and thiols indicated that while preparing gelatinase selective inhibitors was straightforward, there was not an obvious route to selective inhibitors of collagenase-1. Combinatorial libraries were prepared and evaluated for their ability to inhibit collagenase-1 and gelatinase-B substrate hydrolysis. A method for estimating the IC50 values of compounds generated by high-throughput parallel synthesis aided in the identification of compounds with the desired properties. We have found that thiol diketopiperazines derived from nitrophenylalanine are both potent and selective inhibitors of collagenase-1. In addition, we have demonstrated that combinatorial chemistry can be utilized to identify molecules with a desired selectivity profile without access to the traditional tools of rational drug design.

CiteXplore: 10212120

DOI: 10.1021/jm980475p