Discovery and optimization of potency and selectivity of a non-Zn-chelating MMP-13 inhibitor with the aid of protein co-crystal structural information is reported. This inhibitor was observed to have a binding mode distinct from previously published MMP-13 inhibitors. Potency and selectivity were improved by extending the hit structure out from the active site into the S1' pocket.
Boehringer Ingelheim Pharmaceuticals, Department of Medicinal Chemistry, 900 Ridgebury Rd, Ridgefield, CT 06877, USA. alexander.heim-riether@boehringer-ingelheim.com
