Tavares Francis X, Boncek Virginia, Deaton David N, Hassell Anne M, Long Stacey T, Miller Aaron B, Payne Alan A, Miller Larry R, Shewchuk Lisa M, Wells-Knecht Kevin, Willard Derril H, Wright Lois L, Zhou Hui-Qiang
Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA.
J Med Chem. 2004 Jan 29;47(3):588-99. doi: 10.1021/jm030373l.
Osteoclast-mediated bone matrix resorption has been attributed to cathepsin K, a cysteine protease of the papain family that is abundantly and selectively expressed in osteoclast. Inhibition of cathepsin K could potentially be an effective method to prevent osteoporosis. Structure-activity studies on a series of reversible ketoamides based inhibitors of cathepsin K have led to identification of potent and selective compounds. Crystallographic studies have given insights into the mode of binding of these inhibitors. A series of ketoamides with varying P1 moieties were first synthesized to find an optimum group that would fit into the S1 subsite of the cysteine protease, cathepsin K. With a desired P1 group in place a variety of heterocyclic analogues in the P' region were synthesized to study their steric and electronic effects. In the process of exploring these P' heterocyclic variations, excellent selectivity was gained over other highly homologous cysteine proteases, including cathepsins L, S, and V. The favorable pharmacokinetic properties of some of these cathepsin K inhibitors in rats make them suitable for evaluation in rodent osteoporosis models. A representative cathepsin K inhibitor was shown to attenuate PTH-stimulated hypercalcemia in the TPTX rat model. These inhibitors provide a viable lead series in the discovery of new therapies for the prevention and treatment of osteoporosis
破骨细胞介导的骨基质吸收被认为与组织蛋白酶K有关，它是木瓜蛋白酶家族的一种半胱氨酸蛋白酶，在破骨细胞中大量且选择性地表达。抑制组织蛋白酶K可能是预防骨质疏松症的有效方法。对一系列基于可逆酮酰胺的组织蛋白酶K抑制剂进行的构效关系研究，已鉴定出强效且选择性的化合物。晶体学研究深入了解了这些抑制剂的结合模式。首先合成了一系列具有不同P1部分的酮酰胺，以找到一个适合半胱氨酸蛋白酶组织蛋白酶K的S1亚位点的最佳基团。在确定了所需的P1基团后，合成了P'区域的各种杂环类似物，以研究它们的空间和电子效应。在探索这些P'杂环变体的过程中，相对于其他高度同源的半胱氨酸蛋白酶，包括组织蛋白酶L、S和V，获得了优异的选择性。其中一些组织蛋白酶K抑制剂在大鼠中具有良好的药代动力学特性，使其适合在啮齿动物骨质疏松模型中进行评估。在TPTX大鼠模型中，一种代表性的组织蛋白酶K抑制剂被证明可减轻甲状旁腺激素刺激的高钙血症。这些抑制剂为发现预防和治疗骨质疏松症的新疗法提供了一个可行的先导系列。
