{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T06:28:41Z","timestamp":1789972121972,"version":"4.0.1"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2024,2,10]],"date-time":"2024-02-10T00:00:00Z","timestamp":1707523200000},"content-version":"vor","delay-in-days":2514,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007903","name":"Bloodwise","doi-asserted-by":"publisher","award":["UK 12053"],"award-info":[{"award-number":["UK 12053"]}],"id":[{"id":"10.13039\/501100007903","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004357","name":"Procter and Gamble","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004357","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,9,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>\u2003<\/jats:title><jats:p>Bisphosphonates are widely used in the treatment of clinical disorders characterized by increased bone resorption, including osteoporosis, Paget's disease, and the skeletal complications of malignancy. The antiresorptive potency of the nitrogen-containing bisphosphonates on bone in vivo is now recognized to depend upon two key properties, namely mineral binding affinity and inhibitory activity on farnesyl pyrophosphate synthase (FPPS), and these properties vary independently of each other in individual bisphosphonates. The better understanding of structure activity relationships among the bisphosphonates has enabled us to design a series of novel bisphosphonates with a range of mineral binding properties and antiresorptive potencies. Among these is a highly potent bisphosphonate, 1-fluoro-2-(imidazo-[1,2 alpha]pyridin-3-yl)-ethyl-bisphosphonate, also known as OX14, which is a strong inhibitor of FPPS, but has lower binding affinity for bone mineral than most of the commonly studied bisphosphonates. The aim of this work was to characterize OX14 pharmacologically in relation to several of the bisphosphonates currently used clinically. When OX14 was compared to zoledronate (ZOL), risedronate (RIS), and minodronate (MIN), it was as potent at inhibiting FPPS in vitro but had significantly lower binding affinity to hydroxyapatite (HAP) columns than ALN, ZOL, RIS, and MIN. When injected i.v. into growing Sprague Dawley rats, OX14 was excreted into the urine to a greater extent than the other bisphosphonates, indicating reduced short-term skeletal uptake and retention. In studies in both Sprague Dawley rats and C57BL\/6J mice, OX14 inhibited bone resorption, with an antiresorptive potency equivalent to or greater than the comparator bisphosphonates. In the JJN3-NSG murine model of myeloma-induced bone disease, OX14 significantly prevented the formation of osteolytic lesions (p\u2009&amp;lt;\u20090.05). In summary, OX14 is a new, highly potent bisphosphonate with lower bone binding affinity than other clinically relevant bisphosphonates. This renders OX14 an interesting potential candidate for further development for its potential skeletal and nonskeletal benefits. \u00a9 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jbmr.3138","type":"journal-article","created":{"date-parts":[[2017,3,24]],"date-time":"2017-03-24T13:09:48Z","timestamp":1490360988000},"page":"1860-1869","source":"Crossref","is-referenced-by-count":27,"title":["The Pharmacological Profile of a Novel Highly Potent Bisphosphonate, OX14 (1-Fluoro-2-(Imidazo-[1,2-\u03b1]Pyridin-3-yl)-Ethyl-Bisphosphonate)"],"prefix":"10.1093","volume":"32","author":[{"given":"Michelle A","family":"Lawson","sequence":"first","affiliation":[{"name":"Mellanby Centre for Bone ResearchMedical SchoolUniversity of SheffieldUK"},{"name":"Department of Oncology and MetabolismMedical SchoolUniversity of SheffieldUK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank H","family":"Ebetino","sequence":"additional","affiliation":[{"name":"Department of ChemistryUniversity of RochesterRochesterNYUSA"},{"name":"Mellanby Centre for Bone ResearchMedical SchoolUniversity of SheffieldUK"},{"name":"Department of Oncology and MetabolismMedical SchoolUniversity of SheffieldUK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Mazur","sequence":"additional","affiliation":[{"name":"TWI Chem LLCMasonOHUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew D","family":"Chantry","sequence":"additional","affiliation":[{"name":"Mellanby Centre for Bone ResearchMedical SchoolUniversity of SheffieldUK"},{"name":"Department of Oncology and MetabolismMedical SchoolUniversity of SheffieldUK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Paton-Hough","sequence":"additional","affiliation":[{"name":"Mellanby Centre for Bone ResearchMedical SchoolUniversity of SheffieldUK"},{"name":"Department of Oncology and MetabolismMedical SchoolUniversity of SheffieldUK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly R","family":"Evans","sequence":"additional","affiliation":[{"name":"Mellanby Centre for Bone ResearchMedical SchoolUniversity of SheffieldUK"},{"name":"Department of Oncology and MetabolismMedical SchoolUniversity of SheffieldUK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darren","family":"Lath","sequence":"additional","affiliation":[{"name":"Mellanby Centre for Bone ResearchMedical SchoolUniversity of SheffieldUK"},{"name":"Department of Oncology and MetabolismMedical SchoolUniversity of SheffieldUK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria K","family":"Tsoumpra","sequence":"additional","affiliation":[{"name":"Mellanby Centre for Bone ResearchMedical SchoolUniversity of SheffieldUK"},{"name":"Department of Oncology and MetabolismMedical SchoolUniversity of SheffieldUK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark W","family":"Lundy","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell BiologyIndiana UniversityIndianapolisINUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy LM","family":"Dobson","sequence":"additional","affiliation":[{"name":"Procter & GambleMasonOHUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Quijano","sequence":"additional","affiliation":[{"name":"Procter & GambleMasonOHUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron A","family":"Kwaasi","sequence":"additional","affiliation":[{"name":"Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal SciencesThe Oxford University Institute of Musculoskeletal SciencesThe Botnar Research CentreNuffield Orthopaedic CentreOxfordUK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James E","family":"Dunford","sequence":"additional","affiliation":[{"name":"Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal SciencesThe Oxford University Institute of Musculoskeletal SciencesThe Botnar Research CentreNuffield Orthopaedic CentreOxfordUK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuchen","family":"Duan","sequence":"additional","affiliation":[{"name":"Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal SciencesThe Oxford University Institute of Musculoskeletal SciencesThe Botnar Research CentreNuffield Orthopaedic CentreOxfordUK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James T","family":"Triffitt","sequence":"additional","affiliation":[{"name":"Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal SciencesThe Oxford University Institute of Musculoskeletal SciencesThe Botnar Research CentreNuffield Orthopaedic CentreOxfordUK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwyn","family":"Jeans","sequence":"additional","affiliation":[{"name":"Procter & GambleMasonOHUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R Graham 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