title: The biphenyl-carboxylate derivative ABD328 is a novel orally active antiresorptive agent.
abstract: We previously described a novel series of biphenyl carboxylic acid derivatives which have potent antiresorptive effects in vitro and in vivo and do not affect osteoblast function. However, none of the previous compounds showed oral activity, probably because they were esters, which would be expected to be metabolized very rapidly. Here, we tested whether derivatives where the ester link was replaced by a ketone link were orally active. Compounds were tested in murine osteoclast and osteoblast cultures and in the mouse ovariectomy (OVX) model of osteoporosis. The ketones were at least as potent at inhibiting osteoclast formation and RANKL signaling in vitro as the esters and did not inhibit osteoblast differentiation or function. The basic ketone-linked compound ABD68 was only partially able to inhibit OVX-induced bone loss at an oral dose of 20 mg/kg daily. Substitutions on the phenyl rings increased the potency of the compounds in vitro and may prevent metabolism of the compounds in vivo. The most promising derivative, ABD328, completely prevented OVX-induced bone loss when administered by intraperitoneal injection at 3 mg/kg daily. Furthermore, ABD328 was also able to fully prevent OVX-induced bone loss when given orally at 10 mg/kg daily. The results indicate that biphenyl carboxylates like ABD328 are oral candidate drugs for the treatment of diseases characterized by increased bone resorption, such as postmenopausal osteoporosis.
authors.affiliation: Rheumatic Diseases Unit, Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK. aymen.idris@ed.ac.uk
authors.forename: Aymen I
authors.initials: AI
authors.lastname: Idris
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Coste
authors.forename: Iain R
authors.initials: IR
authors.lastname: Greig
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Ralston
authors.forename: Rob J
authors.initials: RJ
authors.lastname: van't Hof
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001862:Bone Resorption / Q000517:prevention & control*; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D010024:Osteoporosis / Q000188:drug therapy / Q000517:prevention & control; D010052:Ovariectomy; D053245:RANK Ligand / Q000378:metabolism
chemical_list: D001713:Biphenyl Compounds; D050071:Bone Density Conservation Agents; D053245:RANK Ligand; C556521:ABD 328; C010574:biphenyl