Identification of biphenylcarboxylic acid derivatives as a novel class of bone resorption inhibitors.
A novel class of biphenylcarboxylic acid derivatives are described that inhibit osteoclastic bone resorption in vitro by promoting osteoclast apoptosis and that prevent ovariectomy-induced bone loss in vivo. The compounds act by a novel mechanism that seems to be distinct from existing antiresorptive drugs.


BACKGROUND
Many common bone diseases such as osteoporosis, Paget's disease, and cancer-associated bone disease are characterized by excessive bone loss caused by increased osteoclastic activity. Successful treatment of these diseases is based on osteoclast inhibition. The osteoclast inhibitory drugs that are currently available fall into relatively few mechanistic classes, indicating the need to identify novel antiresorptives. Here we describe a series of biphenylcarboxylic acid derivatives that have potent inhibitory effects on osteoclastic bone resorption in vitro and on ovariectomy-induced bone loss in vivo.


METHODS
Compounds were tested for inhibitory effects on bone resorption in vitro using mouse osteoblast-bone marrow co-cultures, isolated rabbit osteoclasts, and mouse osteoclasts generated from bone marrow. Some experiments were also performed on human osteoclasts generated from peripheral blood mononuclear cells. We also investigated the effects of specific compounds on ovariectomy-induced bone loss in vivo in mice.


RESULTS
One of the most potent compounds identified was the butanediol ester of biphenyl carboxylic acid (ABD056), which inhibited osteoclast formation in mouse osteoblast-bone marrow co-cultures by 50% (IC50) at a concentration of 26 microM and in macrophage-colony stimulating factor (M-CSF)- and RANKL-stimulated mouse bone marrow cultures with an IC50 of 8 microM. Mechanistic studies showed that ABD056 caused osteoclast apoptosis and inhibited TNFalpha-induced NF-kappaB activation. No inhibitory effects on osteoblast growth or differentiation were observed at concentrations of up to 100 microM. When administered to mice at doses of 5 and 10 mg/kg/day, ABD056 prevented ovariectomy-induced bone loss.


CONCLUSIONS
Butanediol biphenylcarboxylic acid derivatives represent a new class of antiresorptive drug that might be of therapeutic value in the prevention and treatment of diseases characterized by osteoclast activation such as osteoporosis, cancer-associated bone disease, and Paget's disease of bone.
Van 't Hof
Rob J
RJ
Bone Research Group, Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
Idris
Aymen I
AI
Ridge
Susan A
SA
Dunford
James
J
Greig
Iain R
IR
Ralston
Stuart H
SH
D000469:Alkaline Phosphatase / Q000187:drug effects; D000818:Animals; D017209:Apoptosis; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy*; D002264:Carboxylic Acids / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis; D002478:Cells, Cultured; D020672:I-kappa B Proteins; D066298:In Vitro Techniques; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects*; D010052:Ovariectomy; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020827:rap1 GTP-Binding Proteins / Q000187:drug effects
D001713:Biphenyl Compounds; D002264:Carboxylic Acids; D020672:I-kappa B Proteins; D014409:Tumor Necrosis Factor-alpha; D011451:Prostaglandin-Endoperoxide Synthases; D000469:Alkaline Phosphatase; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D020827:rap1 GTP-Binding Proteins