Gustin Darin J, Sehon Clark A, Wei Jianmei, Cai Hui, Meduna Steven P, Khatuya Haripada, Sun Siquan, Gu Yin, Jiang Wen, Thurmond Robin L, Karlsson Lars, Edwards James P
Johnson and Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.
Bioorg Med Chem Lett. 2005 Mar 15;15(6):1687-91. doi: 10.1016/j.bmcl.2005.01.045.
A novel series of competitive, reversible cathepsin S (CatS) inhibitors was discovered and optimized. The 4-(2-keto-1-benzimidazolinyl)-piperidin-1-yl moiety was found to be an effective replacement for the 4-arylpiperazin-1-yl group found in our earlier series of CatS inhibitors. This replacement imparted improved PK properties as well as decreased off-target activity. Optimization of the ketobenzimidazole moiety led to the discovery of the lead compound JNJ 10329670, which represents a novel class of selective, noncovalent, reversible, and orally bioavailable inhibitors of cathepsin S.
发现并优化了一系列新型的竞争性、可逆性组织蛋白酶S（CatS）抑制剂。发现4-(2-氧代-1-苯并咪唑啉基)-哌啶-1-基部分可有效替代我们早期系列CatS抑制剂中的4-芳基哌嗪-1-基部分。这种替代赋予了更好的药代动力学性质以及降低的脱靶活性。对酮苯并咪唑部分的优化导致了先导化合物JNJ 10329670的发现，它代表了一类新型的组织蛋白酶S选择性、非共价、可逆且口服生物可利用的抑制剂。
