Novel Pyrazole Derivatives Effectively Inhibit Osteoclastogenesis, a Potential Target for Treating Osteoporosis
Journal
Journal of Medicinal Chemistry
Journal Volume
58
Journal Issue
12
Pages
4954-4963
Date Issued
2015
Author(s)
Abstract
As human beings live longer, age-related diseases such as osteoporosis will become more prevalent. Intolerant side effects and poor responses to current treatments are observed. Therefore, novel effective therapeutic agents are greatly needed. Here, pyrazole derivatives were designed and synthesized, and their osteoclastogenesis inhibitory effects both in vitro and in vivo were evaluated. The most promising compound 13 with a 2-(dimethylamino)ethyl group inhibited markedly in vitro osteoclastogenesis as well as the bone resorption activity of osteoclasts. Compound 13 affected osteoclasts early proliferation and differentiation more than later fusion and maturation stages. In ovariectomized (OVX) mice, compound 13 can inhibit the loss of trabecular bone volume, trabecular bone number, and trabecular thickness. Moreover, compound 13 can antagonize OVX-induced reduction of serum bone resorption marker and then compensatory increase of the bone formation marker. To sum up, compound 13 has high potential to be developed into a novel therapeutic agent for treating osteoporosis in the future. ? 2015 American Chemical Society.
SDGs
Other Subjects
2 (dimethylamino)ethyl 5 (1 benzyl 1h indazol 3 yl)furan 2 carboxylate; immunoglobulin enhancer binding protein; osteoclast differentiation factor; pyrazole derivative; unclassified drug; immunoglobulin enhancer binding protein; osteoclast differentiation factor; pyrazole derivative; animal cell; animal experiment; animal model; animal tissue; Article; cell differentiation; cell maturation; cell proliferation; controlled study; drug design; drug synthesis; female; nonhuman; ossification; osteoclast; osteoclastogenesis; osteolysis; ovariectomy-induced osteoporosis; trabecular bone; animal; antagonists and inhibitors; blood; bone density; cell culture; chemistry; drug effects; human; immunology; male; mouse; osteoporosis; ovariectomy; pathology; Sprague Dawley rat; tibia; Animals; Bone Density; Bone Resorption; Cell Differentiation; Cells, Cultured; Female; Humans; Male; Mice; NF-kappa B; Osteoclasts; Osteoporosis; Ovariectomy; Pyrazoles; RANK Ligand; Rats, Sprague-Dawley; Tibia
Type
journal article