Replacing alkyl sulfonamide with aromatic sulfonamide in sulfonamide-type RXR agonists favors switch towards antagonist activity

被引：21

作者：

Morishita, Ken-ichi ^{[1
]}

Yakushiji, Nobumasa ^{[1
]}

Ohsawa, Fuminori ^{[1
]}

Takamatsu, Kayo ^{[1
]}

Matsuura, Nobuyasu ^{[2
]}

Makishima, Makoto ^{[3
]}

Kawahata, Masatoshi ^{[4
]}

Yamaguchi, Kentaro ^{[4
]}

Tai, Akihiro ^{[5
]}

Sasaki, Kenji ^{[1
]}

Kakuta, Hiroki ^{[1
]}

机构：

[1] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Div Pharmaceut Sci, Okayama 7008530, Japan

[2] Okayama Univ Sci, Fac Sci, Okayama 7000005, Japan

[3] Nihon Univ, Sch Med, Dept Biomed Sci, Div Biochem,Itabashi Ku, Tokyo 1738610, Japan

[4] Tokushima Bunri Univ, Kagawa 7692193, Japan

[5] Prefectural Univ Hiroshima, Fac Life & Environm Sci, Shobara 7270023, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 03期

关键词：

Retinoid X receptor; RXR; Antagonists; Molecular design; Sulfonamide; RETINOID-X-RECEPTOR; INHIBITION; RAR; MODULATORS; PREVENTS; MOIETY; CANCER; ACIDS;

D O I：

10.1016/j.bmcl.2008.11.086

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 RXR alpha-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. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：1001 / 1003

页数：3

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