Merck Frosst Centre for Therapeutic Research, Pointe-Claire-Dorval, Que., Canada.
Curr Top Med Chem. 2010;10(7):745-51. doi: 10.2174/156802610791113450.
Cathepsin K (Cat K) is the primary enzyme involved in Type I collagen degradation in bone resorption. The development of a Cat K inhibitor should provide an effective treatment for osteoporosis. Key components of a clinically viable inhibitor are oral bioavailability, high selectivity over related cathepsins, and a covalent, reversible warhead to bind to the active site cysteine of the enzyme. This article reviews recent advances in the design of inhibitors derived from peptidic leads that contain either a ketone or nitrile electrophile. Three of these compounds have progressed into clinical trials and one, odanacatib (5), is currently in Phase III studies for the treatment of post-menopausal osteoporosis.
组织蛋白酶 K（Cat K）是参与骨吸收中 I 型胶原降解的主要酶。Cat K 抑制剂的开发将为骨质疏松症的治疗提供有效的手段。一个具有临床应用前景的抑制剂的关键组成部分是口服生物利用度、对相关组织蛋白酶的高选择性，以及与酶的活性半胱氨酸结合的共价、可逆的弹头。本文综述了从含有酮或腈亲电试剂的肽类先导化合物设计抑制剂的最新进展。其中有 3 种化合物已进入临床试验，一种名为odanacatib（5）的化合物目前正在进行治疗绝经后骨质疏松症的 III 期研究。
