title: Novel nonsecosteroidal vitamin D3 carboxylic acid analogs for osteoporosis, and SAR analysis.
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.
authors.affiliation: Research Division, Chugai Pharmaceutical Co. Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. kashiwagihrt@chugai-pharm.co.jp
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kashiwagi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ono
authors.forename: Kazuki
authors.initials: K
authors.lastname: Shimizu
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Haneishi
authors.forename: Susumu
authors.initials: S
authors.lastname: Ito
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Iijima
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Ichikawa
authors.forename: Suguru
authors.initials: S
authors.lastname: Harada
authors.forename: Hideki
authors.initials: H
authors.lastname: Sato
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sekiguchi
authors.forename: Masaki
authors.initials: M
authors.lastname: Ishigai
authors.forename: Tadakatsu
authors.initials: T
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002117:Calcitriol / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000097:blood; D002460:Cell Line; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D051379:Mice; D015675:Osteocalcin / Q000032:analysis / Q000502:physiology; D010024:Osteoporosis / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000819:agonists / Q000187:drug effects / Q000235:genetics; D013256:Steroids / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D050071:Bone Density Conservation Agents; D018167:Receptors, Calcitriol; D013256:Steroids; D015675:Osteocalcin; D002762:Cholecalciferol; D002117:Calcitriol; D002118:Calcium