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A series of nonsecosteroidal vitamin D receptor agonists for osteoporosis therapy.

Abstract
In an extension of our study on gamma hydroxy carboxylic acid analogs, we explored a series of nonsecosteroidal vitamin D receptor (VDR) agonists in which 1,3-diol of 1,25(OH)2D3 had been replaced by aryl acetic acid. These analogs showed very potent activity in vitro compared with 1,25(OH)2D3. An X-ray analysis of 8d showed that the inserted phenyl ring well mimicked the folded methylene linker of the gamma hydroxy carboxylic acid moiety but the carboxylic acid of 8d interacted with VDR in a different manner from gamma hydroxy carboxylic acids. Through our in vivo screening in an osteoporosis rat model using immature rats, we identified a potent active vitamin D3 analog, compound 7e. In mature rats of the same model, compound 7e also showed good PK profiling and excellent ability to prevent bone mineral density loss without severe hypercalcemia. Our nonsecosteroidal VDR agonist 7e (CH5036249) could be a possible new drug candidate for treating osteoporosis in human.
AuthorsHirotaka Kashiwagi, Yoshiyuki Ono, Masateru Ohta, Susumu Itoh, Fumihiko Ichikawa, Suguru Harada, Satoshi Takeda, Nobuo Sekiguchi, Masaki Ishigai, Tadakatsu Takahashi
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 21 Issue 7 Pg. 1823-33 (Apr 01 2013) ISSN: 1464-3391 [Electronic] England
PMID23453218 (Publication Type: Journal Article)
CopyrightCopyright © 2013 Elsevier Ltd. All rights reserved.
Chemical References
  • Benzhydryl Compounds
  • CH 5036249
  • Pyridines
  • Receptors, Calcitriol
  • Osteocalcin
  • Cholecalciferol
Topics
  • Animals
  • Benzhydryl Compounds (chemistry, pharmacokinetics, pharmacology, therapeutic use)
  • Bone Density (drug effects)
  • Cell Line
  • Cholecalciferol (analogs & derivatives, pharmacokinetics, pharmacology, therapeutic use)
  • Crystallography, X-Ray
  • Humans
  • Male
  • Models, Molecular
  • Molecular Docking Simulation
  • Osteocalcin (metabolism)
  • Osteoporosis (drug therapy, metabolism)
  • Pyridines (chemistry, pharmacokinetics, pharmacology, therapeutic use)
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Calcitriol (agonists, metabolism)

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