Identification of novel biphenyl carboxylic acid derivatives as novel antiresorptive agents that do not impair parathyroid hormone-induced bone formation.
Bisphosphonates are widely used in the treatment of osteoporosis, but they inhibit bone formation and blunt the anabolic effect of PTH. Here we describe a novel series of compounds that have potent antiresorptive effects in vitro and in vivo that do not adversely affect osteoblast function. The effects of the compounds on osteoclast formation and survival were studied on mouse osteoclasts generated from bone marrow macrophages and on osteoblast function using primary mouse calvarial osteoblast cultures and bone nodule cultures. Studies were performed in vivo using sham-operated or ovariectomized mice. The most potent compound tested was ABD350, a halogen-substituted derivative of the parent compound ABD56 in which the labile ester bond was replaced by a reduced ketone link, with IC50 osteoclast formation at a concentration of 1.3 microm. All compounds inhibited receptor activator of nuclear factor-kappaB ligand-induced inhibitor of nuclear factor kappaB phosphorylation and caused osteoclast apoptosis but no inhibitory effects on osteoblast function were observed at concentrations of up to 20 microm. ABD350 prevented ovariectomy-induced bone loss when given ip (5 mg/kg.d), whereas ABD56 was only partially effective at this dose. In contrast to the bisphosphonate alendronate, ABD350 had no inhibitory effect on PTH-induced bone formation in ovariectomized mice. In conclusion, the biphenyl carboxylic acid derivatives like ABD350 represent a new class of antiresorptive drugs that inhibit osteoclast activity but have no significant inhibitory effects on osteoblast activity in vitro or PTH-induced bone formation in vivo.
Idris
Aymen I
AI
Rheumatic Diseases Unit, Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom.
Greig
Iain R
IR
Bassonga-Landao
Euphemie
E
Ralston
Stuart H
SH
van 't Hof
Rob J
RJ
D019386:Alendronate / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001565:Benzoates / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology; D001862:Bone Resorption / Q000209:etiology; D005260:Female; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D051379:Mice; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D010012:Osteogenesis / Q000187:drug effects*; D010052:Ovariectomy / Q000009:adverse effects; D010281:Parathyroid Hormone / Q000494:pharmacology*; D012886:Skull
D001565:Benzoates; D001713:Biphenyl Compounds; D010281:Parathyroid Hormone; C529241:biphenylcarboxylic acid butanediol ester; D016173:Macrophage Colony-Stimulating Factor; D019386:Alendronate