Phosphinic acid-based MMP-13 inhibitors that spare MMP-1 and MMP-3

Phosphinic acid-based inhibitors of MMP-13 have been investigated with the aim of identifying potent inhibitors with high selectivity versus MMP-1. Independent variation of the substituents on a P-1' phenethyl group and a P-2 benzyl group improved potencies in both cases around 3-fold over the unsubstituted parent. Combining improved P-1' and P-2 groups into a single molecule gave an inhibitor with a 4.5 nM IC50 against MMP-13 and which is 270-fold selective over MMP-1. (C) 2003 Elsevier Science Ltd. All rights reserved.