title: Synthesis, metabolism, and biological activity of 2-[3-(tetrazolyl)propyl]-1α,25-dihydroxy-19-norvitamin D3.
abstract: Recently, we found that 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D3showed higher osteocalcin promoter transactivation activity in human osteosarcoma (HOS) cells and a greater therapeutic effect in ovariectomized (OVX) rats in vivo than those of active vitamin D3, 1α,25(OH)2D3. We were interested in introducing a heterocyclic ring to the C2 position of the seco-steroidal structure via an alkyl linker, and four novel C2-(3-tetrazolylpropyl) substituted 1α,25-dihydroxy-19-norvitamin D3analogs, 2α-[3-(tetrazol-1-yl)propyl]-, 2β-[3-(tetrazol-1-yl)propyl]-, 2α-[3-(tetrazol-2-yl)propyl]-, and 2β-[3-(tetrazol-2-yl)propyl]-19-nor-1α,25(OH)2D3were synthesized. Among them, 2α-[3-(tetrazol-1-yl)propyl]-19-nor-1α,25(OH)2D3showed weak binding affinity for human vitamin D receptor (hVDR) (2.6% of 1α,25(OH)2D3and ca. 15% of 19-nor-1α,25(OH)2D3) and weak VDR transactivation activity in HOS cells (EC507.3nM, when 1α,25(OH)2D30.23nM). Although the other three compounds could not act as VDR binders by evaluation of the competition assays, 2α-[3-(tetrazol-2-yl)propyl]-19-nor-1α,25(OH)2D3showed weak transactivation activity (EC5012.5nM). Metabolic stability of the 2α-substituted compounds 2α-[3-(tetrazol-1-yl)propyl]- and 2α-[3-(tetrazol-2-yl)propyl]-19-nor-1α,25(OH)2D3was higher than that of the 2β-substituted counterparts 2β-[3-(tetrazol-1-yl)propyl]- and 2β-[3-(tetrazol-2-yl)propyl]-19-nor-1α,25(OH)2D3against human CYP24A1. Introduction of a tetrazole ring to the C2-position of the 19-norvitamin D3skeleton with the propyl linker led to weak VDR agonistic activity with stability against CYP24A1 metabolism.
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Takano
authors.affiliation: Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama 939-0398, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Yasuda
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan.
authors.forename: Erika
authors.initials: E
authors.lastname: Higuchi
authors.affiliation: Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama 939-0398, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Tohyama
authors.affiliation: Teijin Institute for Bio-medical Research, Teijin Pharma Ltd., Hino, Tokyo 191-8512, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Takeuchi
authors.affiliation: Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama 939-0398, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaki
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan. Electronic address: akittaka@pharm.teikyo-u.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kittaka
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D015195:Drug Design; D005030:Ethylenes / Q000737:chemistry; D006801:Humans; D015675:Osteocalcin / Q000235:genetics; D010024:Osteoporosis / Q000188:drug therapy; D012516:Osteosarcoma / Q000378:metabolism*; D010052:Ovariectomy; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry; D015533:Transcriptional Activation; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics
chemical_list: C114865:1-hydroxy-19-norvitamin D3; C000620963:2-(3-(tetrazolyl)propyl)-1,25-dihydroxy-19-norvitamin D3; D005030:Ethylenes; D018167:Receptors, Calcitriol; D011994:Recombinant Proteins; D013777:Tetrazoles; C579457:VDR protein, human; D015675:Osteocalcin; C036216:ethylene; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol
keywords: 19-Norvitamin D(3) analog; CYP24A1; Metabolism; Synthesis; Transactivation; Vitamin D receptor