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

Abstract 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 IC 50 against MMP-13 and which is 270-fold selective over MMP-1.