title: Discovery of coumarin-dihydropyridine hybrids as bone anabolic agents.
abstract: 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.
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute-CSIR-CDRI, Lucknow 226001, India. kv_sashidhara@cdri.res.in
authors.forename: Koneni V
authors.initials: KV
authors.lastname: Sashidhara
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
authors.forename: Vikram
authors.initials: V
authors.lastname: Khedgikar
authors.forename: Priyanka
authors.initials: P
authors.lastname: Kushwaha
authors.forename: Ram K
authors.initials: RK
authors.lastname: Modukuri
authors.forename: Abdhesh
authors.initials: A
authors.lastname: Kumar
authors.forename: Jyoti
authors.initials: J
authors.lastname: Gautam
authors.forename: Divya
authors.initials: D
authors.lastname: Singh
authors.forename: Balasubramaniam
authors.initials: B
authors.lastname: Sridhar
authors.forename: Ritu
authors.initials: R
authors.lastname: Trivedi
mesh_terms: D000284:Administration, Oral; D045930:Anabolic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy / Q000503:physiopathology; D001842:Bone and Bones / Q000187:drug effects* / Q000502:physiology; D002113:Calcification, Physiologic / Q000187:drug effects; D002454:Cell Differentiation; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D010052:Ovariectomy; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D045930:Anabolic Agents; D015415:Biomarkers; D003374:Coumarins; D004095:Dihydropyridines; D015363:Quinolones; C579724:ethyl 4-(8-sec-butyl-3-(methoxycarbonyl)-2-oxo-2H-chromen-6-yl)-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate