Potent, selective spiropyrrolidine pyrimidinetrione inhibitors of MMP-13

Abstract

Explorations in the pyrimidinetrione series of MMP-13 inhibitors led to the discovery of a series of spiro-fused compounds that are potent and selective inhibitiors of MMP-13. While other spiro-fused motifs are hydrolytically unstable, presumably due to electronic destabilization of the pyrimidinetrione ring, the spiropyrrolidine series does not share this liability. Greater than 100-fold selectivity versus other MMP family members was achieved by incorporation of an extended aryl–heteroaryl P1′group. When dosed as the sodium salt, these compounds displayed excellent oral absorption and pharmacokinetic properties. Despite the selectivity, a representative of this series produced fibroplasia in a 14 day rat study.