title: RXR partial agonist produced by side chain repositioning of alkoxy RXR full agonist retains antitype 2 diabetes activity without the adverse effects.
abstract: We previously reported RXR partial agonist CBt-PMN (1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid: 5, EC50 = 143 nM, Emax = 75%), which showed a potent glucose-lowering effect without causing serious adverse effects. However, it remains important to elucidate the structural requirements for RXR efficacy and the glucose-lowering effect because RXR-permissive heterodimers such as PPAR/RXR or LXR/RXR are reported to be activated differently depending upon the chemical structure of RXR agonists. In this work, we show that an RXR partial agonist, NEt-4IB (6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: 8b, EC50 = 169 nM, Emax = 55%), can be obtained simply by repositioning the side chains (interchanging the isobutoxy and isopropoxy groups) at the hydrophobic moiety of the RXR full agonist NEt-3IB (6-[ethyl-(3-isobutoxy-4-isopropylphenyl)amino]pyridine-3-carboxylic acid: 7b, EC50 = 19 nM). NEt-4IB (8b) showed antitype 2 diabetes activity without the above side effects upon repeated oral administration to mice at 10 mg/kg/day, similarly to 5.
authors.affiliation: Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 1-1-1, Tsushima-naka, Kita-ku Okayama 700-8530, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Kawata
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Morishita
authors.forename: Mariko
authors.initials: M
authors.lastname: Nakayama
authors.forename: Shoya
authors.initials: S
authors.lastname: Yamada
authors.forename: Toshiki
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Furusawa
authors.forename: Sakae
authors.initials: S
authors.lastname: Arimoto-Kobayashi
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Oohashi
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Naitou
authors.forename: Erika
authors.initials: E
authors.lastname: Ishitsubo
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Tokiwa
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tai
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kakuta
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005260:Female; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D017207:Rats, Sprague-Dawley; D047488:Retinoid X Receptors / Q000819:agonists*
chemical_list: D007004:Hypoglycemic Agents; D047488:Retinoid X Receptors