TY - JOUR
T1 - Replacing alkyl sulfonamide with aromatic sulfonamide in sulfonamide-type RXR agonists favors switch towards antagonist activity
AU - Morishita, Ken ichi
AU - Yakushiji, Nobumasa
AU - Ohsawa, Fuminori
AU - Takamatsu, Kayo
AU - Matsuura, Nobuyasu
AU - Makishima, Makoto
AU - Kawahata, Masatoshi
AU - Yamaguchi, Kentaro
AU - Tai, Akihiro
AU - Sasaki, Kenji
AU - Kakuta, Hiroki
N1 - Funding Information:
The authors are grateful to the SC-NMR Laboratory of Okayama University for the NMR experiment. We also thank Dr. Kagechika (School of Biomedical Science, Tokyo Medical and Dental University) for kindly providing HX531. This research was partially supported by a Grant-in Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Culture and Sports of Japan (Nos. 17790090 and 20790101), by the subsidy to promote science and technology in the prefectures where nuclear power plants and other power plants are located.
PY - 2009/2/1
Y1 - 2009/2/1
N2 - 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-naphthy l)amino]nicotinic acid (5a) is a moderately RXRα-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.
AB - 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-naphthy l)amino]nicotinic acid (5a) is a moderately RXRα-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.
KW - Antagonists
KW - Molecular design
KW - RXR
KW - Retinoid X receptor
KW - Sulfonamide
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U2 - 10.1016/j.bmcl.2008.11.086
DO - 10.1016/j.bmcl.2008.11.086
M3 - Article
C2 - 19095448
AN - SCOPUS:58849150709
SN - 0960-894X
VL - 19
SP - 1001
EP - 1003
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 3
ER -
