title: Structure-activity relationship of nonsecosteroidal vitamin D receptor modulators.
abstract: The vitamin D receptor (VDR), a receptor for the secosteroid 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], is a promising drug target in the treatment of bone and mineral disorders, cancer, autoimmune disease, infection, and cardiovascular disease. Indeed, approximately 100 nonsecosteroidal VDR modulators (VDRMs) have been developed. Analysis of X-ray crystal structures reveals: (i) nonsecosteroidal VDRMs bind to VDR in a position similar to 1,25(OH)2D3; (ii) hydrogen bond interactions between ligands and VDR are the most important for VDR binding; (iii) hydrophobic interactions and CH-π interactions in aromatic ligands are also important for VDR binding; and (iv) exchange of C-O-C linkage to C-CH2-C linkage in VDRMs increases transactivation activity, probably as a result of an entropic effect of solvation/desolvation of molecules. Several VDRMs have better therapeutic efficacy when compared to 1,25(OH)2D3 in experimental models of cancer and osteoporosis with less induction of hypercalcemia, a major potential adverse effect in the clinical application of VDR ligands.
authors.affiliation: Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan. Electronic address: makishima.makoto@nihon-u.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001190:Arylsulfonates / Q000737:chemistry / Q000494:pharmacology; D001555:Benzene Derivatives / Q000737:chemistry* / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D018167:Receptors, Calcitriol / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000085:Acetates; D001190:Arylsulfonates; D001555:Benzene Derivatives; D001713:Biphenyl Compounds; D002264:Carboxylic Acids; C510201:LY 2108491; C510202:LY 2109866; D008024:Ligands; D018167:Receptors, Calcitriol; D013876:Thiophenes; C526404:YR301
keywords: cancer; crystal structures; hypercalcemia; nuclear receptors; selective VDR modulators; vitamin D receptor