Novartis Institutes for BioMedical Research, Tsukuba, Ibaraki, Japan.
Curr Top Med Chem. 2010;10(7):752-66. doi: 10.2174/156802610791113423.
The recent emergence of osteoporosis as a major health threat in people of advanced age has intensified the search for novel and effective pharmacologic treatments. Given that bone resorption is exceeding bone formation, a reduction in bone mass leads to disease conditions including post-menopausal osteoporosis and tumor-induced osteolysis. Our efforts in this area have focused on the optimization of non-peptidic cathepsin K inhibitors for affinity and selectivity, from an heteroaromatic nitrile as a novel scaffold. This approach has resulted in the discovery of the potent and selective cathepsin K inhibitor, 44. The concentration of cathepsin K inhibitors, including compound 44, in the target tissues such as bone marrow cavity, were predictive parameters for antibone resorptive efficacy in vivo in the rat. The high level of distribution to the bone marrow was also observed for compounds containing pyrrolopyrimidines with novel spiro-structures as the P3 moiety. In a monkey study with the representative inhibitor 44, the antibone resorptive efficacy was detected 8 h after the compound administration. The efficacy persisted throughout the repeated treatment period of 14 days without any evidence for the development of tolerance. This article constitutes a near comprehensive review of the published scientific literature on small molecule non-peptidic inhibitors for cathepsin K developed by Novartis.
随着骨质疏松症在老年人中成为一个主要的健康威胁，人们对新型有效的药物治疗方法的需求日益迫切。由于骨吸收超过了骨形成，骨量减少导致了包括绝经后骨质疏松症和肿瘤诱导性溶骨性疾病等疾病状态。我们在这一领域的努力重点是优化非肽类组织蛋白酶 K 抑制剂的亲和力和选择性，以杂芳腈为新型骨架。这种方法导致了有效的、选择性的组织蛋白酶 K 抑制剂 44 的发现。组织蛋白酶 K 抑制剂（包括化合物 44）在骨髓腔等靶组织中的浓度是体内抗骨吸收疗效的预测参数，在含有新型螺环结构的吡咯并嘧啶的化合物中也观察到了高水平的分布到骨髓。在一项用代表性抑制剂 44 进行的猴子研究中，在化合物给药后 8 小时就检测到了抗骨吸收的疗效。这种疗效在 14 天的重复治疗期间一直持续，没有任何耐药性发展的迹象。本文构成了对诺华开发的用于组织蛋白酶 K 的小分子非肽类抑制剂的已发表科学文献的近乎全面的综述。
