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Orally Bioavailable Cathepsin K inhibitors with Pyrrolopyrimidine Scaffold

Teno, Naoki and Masuya, Keiichi (2010) Orally Bioavailable Cathepsin K inhibitors with Pyrrolopyrimidine Scaffold. Current Topics in Medicinal Chemistry, 10 (7). pp. 752-766. ISSN 1568-0266


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.

Item Type: Article
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Additional Information: I'm invited to be a guest editor for an issue of “Current Topics in Medicinal Chemistry” on “The Medicinal Chemistry of the Cathepsin Cysteine Proteases” I and Prof. Teno are accepted to organize a special issue as Guest Editors
Keywords: Non-peptidic cathepsin K inhibitors, Pyrrolopyrimidine scaffold, Spiro structure, Bone resorption, Bone marrow, C-terminal telopeptide of type I collagen
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Date Deposited: 13 Oct 2015 13:17
Last Modified: 13 Oct 2015 13:17


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