Novel nonsecosteroidal vitamin D3 carboxylic acid analogs for osteoporosis, and SAR analysis

Novel vitamin D3 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-hydrox...

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Veröffentlicht in:	Bioorganic & medicinal chemistry 2011-08, Vol.19 (16), p.4721-4729
Hauptverfasser:	Kashiwagi, Hirotaka, Ono, Yoshiyuki, Shimizu, Kazuki, Haneishi, Tsuyoshi, Ito, Susumu, Iijima, Shigeyuki, Kobayashi, Takamitsu, Ichikawa, Fumihiko, Harada, Suguru, Sato, Hideki, Sekiguchi, Nobuo, Ishigai, Masaki, Takahashi, Tadakatsu
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Biological and medical sciences Bisphenylmethane Bone Density - drug effects Bone Density Conservation Agents - chemical synthesis Bone Density Conservation Agents - chemistry Bone Density Conservation Agents - pharmacology bone resorption Bones, joints and connective tissue. Antiinflammatory agents Calcitriol - analogs & derivatives Calcitriol - chemistry Calcitriol - pharmacology Calcium - blood Cell Line cholecalciferol Cholecalciferol - analogs & derivatives Cholecalciferol - pharmacology Cholecalciferol - therapeutic use Drug Evaluation, Preclinical Female Humans hydrogen bonding Medical sciences Mice Nonsecosteroidal oral administration Osteocalcin - analysis Osteocalcin - physiology Osteoporosis Osteoporosis - drug therapy Osteoporosis - physiopathology pharmacokinetics Pharmacology. Drug treatments Rats Rats, Sprague-Dawley Receptors, Calcitriol - agonists Receptors, Calcitriol - drug effects Receptors, Calcitriol - genetics skeleton Steroids - chemistry Structure-Activity Relationship VDR agonist Vitamin D3 X-radiation
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Zusammenfassung:	Novel vitamin D3 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 D3. 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.
ISSN:	0968-0896 1464-3391
DOI:	10.1016/j.bmc.2011.07.001