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.
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This study was supported in part by grants from the Arthritis Research Campaign UK and Scottish Enterprise and by an ECTS/Amgen fellowship award to A. I. I.
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Idris, Greig, Ralston and van’t Hof are inventors on UK patent WO2004/098582 Ketones and reduced ketones as therapeutic agents for the treatment of bone conditions, held by the University of Aberdeen. Coste has stated no conflict of interest
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Idris, A.I., Coste, E., Greig, I.R. et al. The Biphenyl-Carboxylate Derivative ABD328 is a Novel Orally Active Antiresorptive Agent. Calcif Tissue Int 87, 525–532 (2010). https://doi.org/10.1007/s00223-010-9417-5
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DOI: https://doi.org/10.1007/s00223-010-9417-5