Osteoporosis is a prevalent condition characterized by a reduction in bone mass and a high risk of fracture, particularly among older adults and postmenopausal women [1]. The pathogenesis of osteoporosis involves an imbalance between bone formation and resorption, with resorption exceeding formation, resulting in a net loss of bone mass [2].

Cathepsin K is a lysosomal cysteine protease predominantly expressed in osteoclasts and plays a pivotal role in bone resorption by degrading collagen, a major constituent of the bone matrix. Thus, inhibiting cathepsin K activity has emerged as a promising therapeutic strategy for treating osteoporosis [3,4].

Recently, pharmaceutical companies have extensively investigated cathepsin K inhibitors as potential antiresorptive therapies, the most promising of which have been noted as odanacatib [5], relacatib [6], balicatib [7], and ONO-5334 [8] (Fig. 1). However, clinical development and regulatory approval of these inhibitors have been hampered by safety concerns primarily related to potential side effects and long-term consequences, such as the increased risk of stroke observed with odanacatib [9]. Although many cathepsin K inhibitors demonstrate high selectivity against lysosomal cathepsins B, L, and S in purified enzyme assays, compounds with basic and lipophilic properties often exhibit reduced selectivity owing to lysosomal accumulation and subsequent non-specific interactions with other cathepsins. Therefore, neutral compounds are preferred to minimize potential off-target effects [10,11].

This study aimed to design, synthesize, and evaluate pyrrolopyrimidine-based compounds as selective cathepsin K inhibitors. Additionally, the study sought to identify novel compounds that effectively inhibit cathepsin K without compromising their selectivity, thereby offering potential therapeutic benefits for osteoporosis with a reduced risk of adverse effects.