Replacing alkyl sulfonamide with aromatic sulfonamide in sulfonamide-type RXR agonists favors switch towards antagonist activity.
Retinoid X receptor (RXR) ligands are attractive candidates for clinical application because of their activity against tamoxifen-resistant breast cancer, taxol-resistant lung cancer, metabolic syndrome, and allergy. Though several RXR ligands, especially RXR antagonists, have been reported, the rational molecular design of such compounds is not well advanced. 4-[N-Methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)amino]nicotinic acid (5a) is a moderately RXRalpha-preferential agonist, and we examined the feasibility of replacing the methyl group on the sulfonamide with a longer alkyl chain or an aromatic ring as an approach to produce new RXR antagonists. Several of the resulting benzenesulfonanilide-type compounds showed RXR antagonist activity. This design strategy should be a useful approach for addressing the lack of structure diversity of RXR antagonists.
Morishita
Ken-ichi
K
Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-Naka, Okayama 700-8530, Japan.
Yakushiji
Nobumasa
N
Ohsawa
Fuminori
F
Takamatsu
Kayo
K
Matsuura
Nobuyasu
N
Makishima
Makoto
M
Kawahata
Masatoshi
M
Yamaguchi
Kentaro
K
Tai
Akihiro
A
Sasaki
Kenji
K
Kakuta
Hiroki
H
D001943:Breast Neoplasms / Q000188:drug therapy; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D005786:Gene Expression Regulation; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008175:Lung Neoplasms / Q000188:drug therapy; D008956:Models, Chemical; D008968:Molecular Conformation; D017239:Paclitaxel / Q000494:pharmacology; D047488:Retinoid X Receptors / Q000819:agonists* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology
D008024:Ligands; D047488:Retinoid X Receptors; D013449:Sulfonamides; D017239:Paclitaxel