Cathepsin K (Cat K) is a cysteine protease involved in bone remodeling. In addition to its role in bone biology, Cat K is upregulated in osteoclasts, chondrocytes and synoviocytes in osteoarthritic (OA) disease states making it a potential therapeutic target for disease-modifying OA. Starting from a prior preclinical compound, MK-1256, lead optimization efforts were carried out in the search for potent Cat K inhibitors with improved selectivity profiles with an emphasis on cathepsin F. Herein, we report the SAR studies which led to the discovery of the highly selective oxazole compound 23, which was subsequently shown to inhibit cathepsin K in vivo as measured by reduced levels of urinary C-telopeptide of collagen type I in dog.

组织蛋白酶 K (Cat K) 是一种参与骨重塑的半胱氨酸蛋白酶。除了在骨生物学中的作用外，Cat K 在骨关节炎 (OA) 疾病状态下的破骨细胞、软骨细胞和滑膜细胞中上调，使其成为改善疾病 OA 的潜在治疗靶点。从先前的临床前化合物 MK-1256 开始，进行了先导优化工作，以寻找具有改进选择性的强效 Cat K 抑制剂，重点是组织蛋白酶 F。在此，我们报告了导致发现高选择性恶唑化合物23，随后通过降低狗中 I 型胶原蛋白的尿 C-端肽水平来测量其在体内抑制组织蛋白酶 K。