Pyrrolopyrimidines: A promising scaffold for the development of novel cathepsin K inhibitors

Cathepsin K, a pivotal enzyme in bone resorption, represents a novel target for the treatment of osteoporosis; however, a clinically approved drug targeting this enzyme remains elusive. Despite intensive research by pharmaceutical companies on cathepsin K inhibitors as potential antiresorptive agents for osteoporosis, the clinical development of these inhibitors has been hindered by several obstacles. These hurdles include limited selectivity for cathepsin K over other cathepsin enzymes, unfavorable pharmacokinetic profiles, and safety concerns. Meanwhile, pyrrolopyrimidines have emerged as promising compounds to overcome these limitations. A focused medicinal chemistry campaign successfully identified several pyrrolopyrimidine derivatives as potential leads for preclinical studies. These compounds demonstrated low toxicity and high efficacy in vitro through selective inhibition of cathepsin K without affecting other cathepsin enzymes. This study involved determining the X-ray crystal structure of cathepsin K in complex with the compound, in parallel with structure-activity relationship (SAR) studies. Incorporating a basic residue capable of forming ionic interactions within the side chain of the core pyrrolopyrimidine structure enhanced selectivity for cathepsin K. In particular, analog 9d exhibited a superior selectivity compared to odanacatib. Furthermore, the preclinical compound 9d exhibited promising oral bioavailability of 28.3 %, which, along with a significant reduction in systemic toxicity, further supports the development this compound as an oral therapeutic agent. The promising pharmacokinetic properties and low toxicity of 9d make it an ideal candidate for osteoporosis treatment.