Abstract
Novel vitamin D(3) analogs with carboxylic acid were explored, focusing on a nonsecosteroidal analog, LG190178, with a bisphenyl skeleton. From X-ray analysis of these analogs with vitamin D receptor (VDR), the carboxyl groups had very unique hydrogen bonding interactions in VDR and mimicked 1α-hydroxy group and/or 3β-hydroxy group of 1α,25-dihydroxyvitamin D(3). A highly potent analog, 6a, with good in vitro activity and pharmacokinetic profiles was identified from an SAR study. Compound 6a showed significant prevention of bone loss in a rat osteoporosis model by oral administration.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Bone Density / drug effects
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Bone Density Conservation Agents / chemical synthesis*
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Bone Density Conservation Agents / chemistry
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Bone Density Conservation Agents / pharmacology
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Calcitriol / analogs & derivatives
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Calcitriol / chemistry
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Calcitriol / pharmacology
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Calcium / blood
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Cell Line
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Cholecalciferol / analogs & derivatives*
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Cholecalciferol / pharmacology
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Cholecalciferol / therapeutic use
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Drug Evaluation, Preclinical
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Female
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Humans
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Mice
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Osteocalcin / analysis
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Osteocalcin / physiology
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Osteoporosis / drug therapy*
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Osteoporosis / physiopathology
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Rats
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Rats, Sprague-Dawley
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Receptors, Calcitriol / agonists
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Receptors, Calcitriol / drug effects
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Receptors, Calcitriol / genetics
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Steroids / chemistry
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Structure-Activity Relationship
Substances
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Bone Density Conservation Agents
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Receptors, Calcitriol
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Steroids
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Osteocalcin
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Cholecalciferol
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Calcitriol
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Calcium