Structure-based design of orally bioavailable cathepsin K inhibitors

Abstract

Cathepsin K, a cysteine protease of the papain superfamily, has been implicated in the process of bone resorption and is therefore a promising therapeutic target for the treatment of diseases characterized by excessive bone loss, such as osteoporosis. We have recently reported the design of two new classes of potent, selective, leucine-based cathepsin K inhibitors based on diacyl carbohydrazide and diacyl hydrazine scaffolds. Using binding models derived from X-ray crystal structures of cathepsin K/inhibitor complexes, inhibitors contg. peptidomimetic elements to replace the Cbz-leucine residues have been designed. The binding models used in the design have been very predictive of relative inhibitor potency. Furthermore, these modifications have ultimately resulted in the identification of compds. with enhanced oral bioavailability. The design and synthesis of these inhibitors, their inhibition of cathepsin K, modeling and crystallog. studies, and preliminary pharmacokinetic data will be discussed.