molecules of the month

Context. “Compound 23” (Merck) is a selective oral cathepsin K (CatK) inhibitor intended for osteoarthritis.  Osteoarthritis affects around 15% of the population, and current treatments offer only symptom relief, highlighting the need for targeted treatments. Prior to the “compound 23”, several CatK inhibitors had reached clinical development: relacatib (GSK), balicatib (Novartis), ONO-5334 (Ono Pharmaceuticals), and odanacatib (Merck). Merck’s preclinical compound MK-1256 was only 40-fold selective, so they set out to develop a compound with at least 1000-fold selectivity for CatK over other biologically relevant cathepsins, using MK-1256 as a starting point.  Target. CatK is a dimeric collagen-degrading cysteine protease and plays a key role in bone resorption by osteoclasts. Upregulation of the enzyme has been observed in articular cartilage of…