Cathepsin K inhibitors, 2000 – 2004

Abstract

Cathepsin K is one of eleven cysteine proteases from the papain superfamily known to be expressed in the human genome. Its selective and abundant expression in osteoclasts and critical role in the degradative phase of bone remodelling suggests that selective inhibition of cathepsin K may provide an effective therapy for the treatment of osteoporosis. This hypothesis has generated considerable interest over the past decade in the development of selective cathepsin K inhibitors. Around 190 cathepsin K-related patent applications have been filed since its discovery in rabbit osteoclasts a decade ago; half of which were published in the last two years, indicating the rapidly increasing level of activity in the field. Small-molecule cathepsin K inhibitors have been reported to show efficacy in animal models of osteoporosis. Most recently, the disclosure from Novartis of the successful completion of Phase IIa trials is likely to attract even greater attention to the target. In addition to a role in bone remodelling, evidence supporting the involvement of cathepsin K in spontaneous rupture of atherosclerotic plaque, leading to arterial thrombosis and potentially fatal myocardial infarction, has also been reported recently. This review is focused on recent advances in the development of specific cathepsin K inhibitors, based on the patent literature from January 2000 to June 2004. Given that rapid advances in this period are directly attributable to the availability of crystallographic data, biostructural information related to key enzyme/inhibitor interactions is also briefly summarised.

• bone resorption
• cathepsin K
• crystallography
• cysteine protease
• inhibitor
• osteoporosis
• structure-based drug design