Discovery of Coumarin鈥揇ihydropyridine Hybrids as Bone Anabolic Agents

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• 作者：Koneni V. Sashidhara ; Manoj Kumar ; Vikram Khedgikar ; Priyanka Kushwaha ; Ram K. Modukuri ; Abdhesh Kumar ; Jyoti Gautam ; Divya Singh ; Balasubramaniam Sridhar ; Ritu Trivedi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：January 10, 2013
• 年：2013
• 卷：56
• 期：1
• 页码：109-122
• 全文大小：663K
• 年卷期：v.56,no.1(January 10, 2013)
• ISSN：1520-4804

文摘

The concept of molecular hybridization led us to discover a novel series of coumarin鈥揹ihydropyridine hybrids that have potent osteoblastic bone formation in vitro and that prevent ovariectomy-induced bone loss in vivo. In this context, among all the compounds screened for alkaline phosphatase activity, four compounds 10, 14, 18, and 22 showed significant activity at picomolar concentrations. A series of other in vitro data strongly suggested compound 18 as the most promising bone anabolic agent, which was further evaluated for in vivo studies. From these studies compound 18 proved to be useful, which at low oral dose of 1 (mg/kg)/day body weight increased bone mass density and volume, expression of osteogenic genes (RUNX2, BMP-2, and ColI), bone formation rate (BFR), and mineral apposition rate (MAR), improved the trabecular microarchitecture, and decreased bone turn over markers in an ovariectomized rodent model for postmenopausal osteoporosis.