Discovery of Coumarin–Dihydropyridine Hybrids as Bone Anabolic Agents

• Published in: Journal of medicinal chemistry 2013-01, Vol.56 (1), p.109-122
• Main Authors: Sashidhara, Koneni V, Kumar, Manoj, Khedgikar, Vikram, Kushwaha, Priyanka, Modukuri, Ram K, Kumar, Abdhesh, Gautam, Jyoti, Singh, Divya, Sridhar, Balasubramaniam, Trivedi, Ritu
• Format: Article
• Language: English
• Subjects: Administration, Oral; Anabolic Agents - chemical synthesis; Anabolic Agents - chemistry; Anabolic Agents - pharmacology; Animals; Biomarkers - metabolism; Bone and Bones - drug effects; Bone and Bones - physiology; Bone Density - drug effects; Bone Resorption - drug therapy; Bone Resorption - physiopathology; Calcification, Physiologic - drug effects; Cell Differentiation; Coumarins - chemical synthesis; Coumarins - chemistry; Coumarins - pharmacology; Crystallography, X-Ray; Dihydropyridines - chemical synthesis; Dihydropyridines - chemistry; Dihydropyridines - pharmacology; Female; Gene Expression - drug effects; Humans; Mice; Osteoblasts - cytology; Osteoblasts - drug effects; Osteoblasts - metabolism; Osteogenesis - drug effects; Osteoporosis, Postmenopausal - drug therapy; Osteoporosis, Postmenopausal - etiology; Osteoporosis, Postmenopausal - physiopathology; Ovariectomy; Quinolones - chemical synthesis; Quinolones - chemistry; Quinolones - pharmacology; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm301281e

The concept of molecular hybridization led us to discover a novel series of coumarin–dihydropyridine 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.