title: Reduction of lipophilicity at the lipophilic domain of RXR agonists enables production of subtype preference: RXRalpha-preferential agonist possessing a sulfonamide moiety.
abstract: Retinoid X receptor agonists (RXR agonists, rexinoids) are interesting candidates for the treatment of cancers such as tamoxifen-resistant breast cancer and taxol-resistant lung cancer. However, well-known RXR agonists possess a strong lipophilic character. In addition, although RXR has three subtypes, no subtype-selective RXR agonists are known. Thus we aimed to produce less-lipophilic and subtype-selective RXR agonists. By designing sulfonamide-type RXR agonists, 4-[N-methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)amino]benzoic acid (8 a) was found to prefer RXRalpha over RXRbeta and RXRgamma, although the potency is less than the potencies of well-known RXR pan-agonists. Moreover, our results suggest that the reduction of lipophilicity at the hydrophobic interaction region of RXR agonists enables production of RXR subtype preference. Our finding will be useful for the creation of more potent and less-lipophilic subtype-selective RXR agonists aimed at the reduction of undesirable side effects.
authors.affiliation: Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-Naka, Okayama 700-8530, Japan.
authors.forename: Kayo
authors.initials: K
authors.lastname: Takamatsu
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takano
authors.forename: Nobumasa
authors.initials: N
authors.lastname: Yakushiji
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Morishita
authors.forename: Nobuyasu
authors.initials: N
authors.lastname: Matsuura
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
authors.forename: Hamed Ismail
authors.initials: HI
authors.lastname: Ali
authors.forename: Eiichi
authors.initials: E
authors.lastname: Akaho
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tai
authors.forename: Kenji
authors.initials: K
authors.lastname: Sasaki
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kakuta
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D019556:COS Cells; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002522:Chlorocebus aethiops; D004357:Drug Synergism; D057927:Hydrophobic and Hydrophilic Interactions; D008956:Models, Chemical; D009580:Nitroblue Tetrazolium / Q000378:metabolism; D010084:Oxidation-Reduction; D047490:Retinoid X Receptor alpha / Q000819:agonists; D049230:Retinoid X Receptor beta / Q000819:agonists; D047491:Retinoid X Receptor gamma / Q000819:agonists; D047488:Retinoid X Receptors / Q000819:agonists*; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D019440:Anti-Obesity Agents; D000970:Antineoplastic Agents; D047490:Retinoid X Receptor alpha; D049230:Retinoid X Receptor beta; D047491:Retinoid X Receptor gamma; D047488:Retinoid X Receptors; D013449:Sulfonamides; D009580:Nitroblue Tetrazolium