title: The first potent subtype-selective retinoid X receptor (RXR) agonist possessing a 3-isopropoxy-4-isopropylphenylamino moiety, NEt-3IP (RXRalpha/beta-dual agonist).
abstract: Retinoid X receptor (RXR) agonists (rexinoids) are attracting much attention for their use in treatment of cancers, including tamoxifen-resistant breast cancer and taxol-resistant lung cancer, and metabolic disease. However, known RXR agonists have a highly lipophilic character. In addition, no subtype-selective RXR agonists have been found. We previously reported an RXRalpha-preferential agonist 4-[N-methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)amino]benzoic acid (6 a). The RXR agonistic activity is much less than that of well-known RXR agonists. To develop potent, less-lipophilic, and subtype-selective RXR agonists, we created new RXR agonists possessing alkoxy and isopropyl groups as a lipophilic domain of the common structure of well-known RXR agonists. As a result, compounds possessing branched alkoxy groups, 6-[N-ethyl-N-(3-isopropoxy-4-isopropylphenyl)amino]nicotinic acid (NEt-3IP: 7 a) and 6-[N-ethyl-N-(3-isobutoxy-4-isopropylphenyl)amino]nicotinic acid (NEt-3IB: 7 c), showed RXR agonistic activity as potent as, or more potent than, the activities of representative RXR agonists. Moreover, NEt-3IP (7 a) was found to be the first RXRalpha/beta-selective (or RXRalpha/beta-dual) agonist. Being potent, less lipophilic, and having RXR subtype-selective activity, NEt-3IP (7 a) is expected to become a new drug candidate and to be a useful biological tool for clarifying each RXR subtype function.
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: Kazunori
authors.initials: K
authors.lastname: Morohashi
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: 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: D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D011407:Propane / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D047490:Retinoid X Receptor alpha / Q000819:agonists* / Q000502:physiology; D049230:Retinoid X Receptor beta / Q000819:agonists* / Q000502:physiology; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000814:Aniline Compounds; D047490:Retinoid X Receptor alpha; D049230:Retinoid X Receptor beta; D011407:Propane