title: Acidic heterocycles as novel hydrophilic pharmacophore of androgen receptor ligands with a carborane core structure.
abstract: A novel series of androgen receptor (AR) ligands bearing an acidic heterocycle with hydrogen-bonding ability as the terminal polar group was developed. Since most non-steroidal AR ligands so far known are structurally limited to nitro- or cyanobenzanilide as the polar pharmacophore, development of alternative hydrogen-bonding components is required to obtain novel AR ligands. Various acidic heterocycles were introduced into a hydrophobic phenylcarborane (1-phenyl-1,12-dicarba-closo-dodecaborane) core structure to provide a moiety that could interact effectively with the critical basic arginine residue of the AR ligand binding domain. The most potent compounds, 1,2,4-oxadiazole-5-thione derivatives 21a and 21b, exhibited higher affinity for hAR than did the well-known anti-androgen hydroxyflutamide. The results suggest that this heterocyclic functionality is potential bioisoster of the nitro and cyano groups forming the polar pharmacophores of known non-steroidal AR ligands.
authors.affiliation: School of Biomedical Science, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan. fujiis.omc@tmd.ac.jp
authors.forename: Shinya
authors.initials: S
authors.lastname: Fujii
authors.forename: Kiminori
authors.initials: K
authors.lastname: Ohta
authors.forename: Tokuhito
authors.initials: T
authors.lastname: Goto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kagechika
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Endo
mesh_terms: D001120:Arginine; D001665:Binding Sites; D001880:Boranes / Q000737:chemistry* / Q000493:pharmacokinetics; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D006860:Hydrogen Bonding; D011944:Receptors, Androgen / Q000378:metabolism*; D013871:Thiones
chemical_list: C410798:AR protein, human; D001880:Boranes; D006571:Heterocyclic Compounds; D011944:Receptors, Androgen; D013871:Thiones; D001120:Arginine