The Biphenyl-Carboxylate Derivative ABD328 is a Novel Orally Active Antiresorptive Agent Aymen I. Idris • Emmanuel Coste • Iain R. Greig • Stuart H. Ralston • Rob J. van’t Hof Received: 20 May 2010 / Accepted: 20 August 2010 / Published online: 18 September 2010 Ó Springer Science+Business Media, LLC 2010 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 com- pounds 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 differ- entiation 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 com- pounds 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. Keywords Osteoclast Á Metabolic bone diseases Á Animal models Á Osteoblast We previously reported the identification of a novel class of biphenyl carboxylic acid derivatives that act as small- molecule inhibitors of osteoclastic bone resorption [1] and have shown that these do not inhibit osteoblast survival or activity both in vitro and in vivo [2]. Inhibitors of bone resorption such as bisphosphonates are the most widely used treatments for common bone diseases such as osteo- porosis [3]. However, bisphosphonates such as alendronate may blunt the bone anabolic effects of parathyroid hor- mone (PTH) [4, 5], indicating a need for bone resorption inhibitors that do not inhibit the anabolic effects of PTH. We have recently shown that, unlike the bisphosphonate alendronate, the biphenyl carboxylic acid derivative ABD350 does not inhibit the bone anabolic actions of PTH [2]. The mechanism of action of the novel compounds is based on the inhibition of RANKL-induced activation of the NFjB and ERK MAP kinase pathways [6], leading to inhibition of osteoclast formation and inducing apoptosis in mature osteoclasts. However, the compounds presented so far were not orally active but were active only when given by intraperitoneal injection. As the original compounds 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 A. I. Idris (&) Á E. Coste Á S. H. Ralston Á R. J. van’t Hof (&) Rheumatic Diseases Unit, Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK A. I. Idris e-mail: aymen.idris@ed.ac.uk URL: www.aymenidris.com R. J. van’t Hof e-mail: rvanthof@staffmail.ed.ac.uk I. R. Greig School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK 123 Calcif Tissue Int (2010) 87:525–532 DOI 10.1007/s00223-010-9417-5