Crane Sheldon N, Black W Cameron, Palmer James T, Davis Dana E, Setti Eduardo, Robichaud Joel, Paquet Julie, Oballa Renata M, Bayly Christopher I, McKay Daniel J, Somoza John R, Chauret Natalie, Seto Carmai, Scheigetz John, Wesolowski Greg, Massé Frederic, Desmarais Sylvie, Ouellet Marc
Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Highway, Kirkland, Quebec, Canada, H9H 3L1.
J Med Chem. 2006 Feb 9;49(3):1066-79. doi: 10.1021/jm051059p.
A new series of nonpeptidic cathepsin K inhibitors that are based on a beta-substituted cyclohexanecarboxamide motif has been developed. Lead optimization yielded compounds with sub-nanomolar potency and exceptional selectivity profiles against cathepsins B, L, and S. Use of fluorine atoms to block metabolism on the cyclohexyl ring led to compounds with excellent pharmacokinetic properties. Considering the well-established role of cathepsin K in osteoclast-mediated bone turnover, compounds such as (-)-34a (hrab Cat K IC(50) 0.28 nM; >800-fold selectivity vs Cat B, L, and S; PK data in dogs: F 55%, t(1/2) = 15 h) exhibit great potential for development as an orally bioavailable therapeutic for treatment of diseases that involve bone loss.
基于β-取代环己烷甲酰胺基序开发了一系列新型非肽类组织蛋白酶K抑制剂。先导化合物优化产生了对组织蛋白酶B、L和S具有亚纳摩尔效力和出色选择性的化合物。使用氟原子阻断环己基环上的代谢，得到了具有优异药代动力学性质的化合物。考虑到组织蛋白酶K在破骨细胞介导的骨转换中已确立的作用，诸如（-）-34a之类的化合物（人源组织蛋白酶K IC50为0.28 nM；对组织蛋白酶B、L和S的选择性大于800倍；犬类药代动力学数据：F 55%，t1/2 = 15小时）作为一种口服生物可利用的治疗涉及骨质流失疾病的药物具有巨大的开发潜力。
