RATIONAL DESIGN AND COMBINATORIAL EVALUATION OF ENZYME-INHIBITOR SCAFFOLDS - IDENTIFICATION OF NOVEL INHIBITORS OF MATRIX METALLOPROTEINASES

The discovery of a novel series of heterocyclic matrix metalloproteina se (MMPs) inhibitors is described. Published crystal structures of pep tidyl hydroxamates bound to MMPs were the basis for the rational desig n of diketopiperazine (DKP) inhibitors. Combinatorial Libraries were p repared and evaluated for their ability to inhibit collagenase-1, stro melysin-1, and gelatinase-B substrate hydrolysis. Deconvolution of act ive pools resulted in the identification of potent inhibitors (IC50's < 100 nM) of collagenase-1 and gelatinase-B, with the most potent inhi bitor exhibiting an IC50 of 30 nM against collagenase-1. A description of the combinatorial evaluation process, as well as initial SAR inter pretation for this novel series, is provided.