3-Piperidylethoxypterocarpan: A potential bone anabolic agent that improves bone quality and restores trabecular micro-architecture in ovariectomized osteopenic rats

• Published in: Molecular and cellular endocrinology Vol. 448; pp. 41 - 54
• Main Authors: Raghuvanshi, Ashutosh, Kumar, Amit, Tyagi, Abdul M., Kureel, Jyoti, Awasthi, Pallavi, Purohit, Deepak, Mansoori, Mohd Nizam, Shukla, Priyanka, Srivastava, Kamini, Gautam, Abnish K., Saxena, Ruchi, Dwivedi, Anila, Singh, Divya, Goel, Atul
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 15.06.2017
• Subjects: Alkaline Phosphatase - metabolism; Anabolic Agents - chemical synthesis; Anabolic Agents - chemistry; Anabolic Agents - pharmacology; Anabolic Agents - therapeutic use; Animals; Benzofurochromene; Biomarkers - metabolism; BMP-2 activator; Bone anabolic agent; Bone Density - drug effects; Bone Diseases, Metabolic - drug therapy; Bone Diseases, Metabolic - pathology; Bone Morphogenetic Protein 2 - secretion; Bone Remodeling - drug effects; Calcification, Physiologic - drug effects; Cancellous Bone - drug effects; Cancellous Bone - pathology; Cell Differentiation - drug effects; Female; Osteoblasts - drug effects; Osteoblasts - metabolism; Osteoblasts - pathology; Osteoporosis; Ovariectomized; Ovariectomy; Phosphorylation - drug effects; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacology; Piperidines - therapeutic use; Pterocarpans - chemical synthesis; Pterocarpans - chemistry; Pterocarpans - pharmacology; Pterocarpans - therapeutic use; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptors, Estrogen - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; BMCs; BMP-2 activator; PTH; ALP; Tb. Pf; BMP-2; T.Ar; BFR; Osteoporosis; μ-CT; T.Pm; BV/TV; Cs.Th; BMD; Benzofurochromene; B.Ar; TFSP; SERM; Ovariectomized; MAPK; Tb. Sp; ER; SMI; OVx; Bone anabolic agent; DA; BFC; MAR
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2017.03.010

A series of new 6H-benzofuro[3, 2-c]chromenes (BFC, pterocarpans) with structure-activity relationships were investigated for their potential use in osteoporosis treatment. One of the BFCs 3-piperidylethoxypterocarpan 20 promotes osteoblast differentiation and mineralization at a dose as low as 1 pM via activation of ER/P38MAPK/BMP-2 pathway. When evaluated for in-vivo osteogenic activity in female Sprague-Dawley rats, BFC 20 increased bone mineral density and new bone formation, compared with control at 1.0 and 10.0 mg/kg/body weight by oral gavage for 30 days. The compound was devoid of any uterotrophic effect and led to the new bone formation in adult ovariectomized osteopenic rats. BFC 20 compound also inhibited bone resorption by reducing Ovx induced increase in urinary CTx, thus exhibiting both bone anabolic and anti-catabolic action. Finally, BFC 20 treatment to Ovx rats led to improved trabecular microarchitectural restoration and exhibited therapeutic potential as a dual acting anti-osteoporotic agent for the management of osteoporosis. •3-piperidylethoxy-pterocarpan20 promotes osteoblast differentiation and mineralization of bone matrix.•Mode of action is via ERα-p38MAPK-BMP2 pathway.•3-piperidylethoxy-pterocarpan20 promotes bone formation and inhibits bone resorption in ovariectomized osteopenic SD rats.