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The Pharmacological Profile of a Novel Highly Potent Bisphosphonate, OX14 (1-Fluoro-2-(Imidazo-[1,2-α]Pyridin-3-yl)-Ethyl-Bisphosphonate).

Authors
  • Lawson, Michelle A1, 2
  • Ebetino, Frank H1, 2, 3
  • Mazur, Adam4
  • Chantry, Andrew D1, 2
  • Paton-Hough, Julia1, 2
  • Evans, Holly R1, 2
  • Lath, Darren1, 2
  • Tsoumpra, Maria K1, 2
  • Lundy, Mark W5
  • Dobson, Roy Lm6
  • Quijano, Michael6
  • Kwaasi, Aaron A7
  • Dunford, James E7
  • Duan, Xuchen7
  • Triffitt, James T7
  • Jeans, Gwyn6
  • Russell, R Graham G1, 2, 7
  • 1 Department of Oncology and Metabolism, Medical School, University of Sheffield, UK.
  • 2 Mellanby Centre for Bone Research, Medical School, University of Sheffield, UK.
  • 3 Department of Chemistry, University of Rochester, Rochester, NY, USA.
  • 4 TWI Chem LLC, Mason, OH, USA.
  • 5 Department of Anatomy and Cell Biology, Indiana University, Indianapolis, IN, USA. , (India)
  • 6 Procter & Gamble, Mason, OH, USA.
  • 7 Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, The Oxford University Institute of Musculoskeletal Sciences, The Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford, UK.
Type
Published Article
Journal
Journal of Bone and Mineral Research
Publisher
Wiley (John Wiley & Sons)
Publication Date
Sep 01, 2017
Volume
32
Issue
9
Pages
1860–1869
Identifiers
DOI: 10.1002/jbmr.3138
PMID: 28337806
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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 < 0.05). 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. © 2017 American Society for Bone and Mineral Research. © 2017 American Society for Bone and Mineral Research.

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