Optimisation of 2-cyano-pyrimidine inhibitors of cathepsin K: Improving selectivity over hERG

Several structure-guided optimisation strategies were explored in order to improve the hERG selectivity profile of cathepsin K inhibitor 1, whilst maintaining its otherwise excellent in vitro and in vivo profile. Ultimately, attenuation of c log P and pKa properties proved a successful approach and led to the discovery of a potent analogue 23, which, in addition to the desired selectivity over hERG (>1000-fold), displayed a highly attractive overall profile.

Structure-guided optimisation strategies which led to a successful attenuation of hERG block in 2-cyano-pyrimidine series of catK inhibitors are described.Figure optionsDownload as PowerPoint slide