title: Vitamin D Analogs with Nitrogen Atom at C2 Substitution and Effect on Bone Formation.
abstract: The Arg274 residue of the ligand binding domain of human vitamin D receptor (hVDR) is important for 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) binding as a specific ligand through forming a hydrogen bond with the 1α-OH group of the active vitamin D3, 1α,25(OH)2D3. An additional pincer-type hydrogen bond formation with Arg274 from a 2α-substituent of a synthetic 1α,25(OH)2D3 analog would enhance the binding affinity and biological activity. A series of 2α-[2-(heteroaryl)ethyl]-, 2α-(4-cyanobutyl)-, 2α-(ω-cyanoalkoxy)-, and 2β-(3-cyanopropoxy)-1α,25(OH)2D3 were designed and synthesized based on our original hVDR super agonists of 2α-(3-hydroxypropyl)- and 2α-(3-hydroxypropoxy)-1α,25(OH)2D3. Their potential biological activities, i.e., hVDR binding affinity, transactivation activity in HOS cells, and therapeutic effect on enhancing the bone mineral density of OVX rats, were studied.
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, Tokyo, Japan. Electronic address: akittaka@pharm.teikyo-u.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kittaka
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Takano
authors.affiliation: Teijin Institute for Bio-medical Research, Teijin Pharma Ltd., Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Saitoh
mesh_terms: D000818:Animals; D001665:Binding Sites; D015519:Bone Density / Q000187:drug effects; D001846:Bone Development / Q000187:drug effects*; D002118:Calcium / Q000097:blood / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D012516:Osteosarcoma / Q000378:metabolism; D010052:Ovariectomy; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D008024:Ligands; D018167:Receptors, Calcitriol; D014807:Vitamin D; D002118:Calcium
keywords: 2α-Functionalized vitamin D; Binding affinity; Bone mineral density; Synthesis; Vitamin D; Vitamin D receptor; X-Ray cocrystallographic analysis