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 RXRα-preferential agonist 4-[N-methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydro-2-naphthyl)amino]benzoic acid (6a). 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 branchedalkoxy groups, 6-[N-ethyl-N-(3-isopropoxy-4-isopropylphenyl) amino]nicotinic acid(NEt-3 IP: 7a) and6-[ N-ethyl-N-(3-isobutoxy-4- isopropylphenyl)amino]nicotinic acid (NEt-3IB : 7c), showed RXR agonistic activity as potent as, or more potent than, the activities of representative RXR agonists. Moreover, NEt-3IP (7a) was found to be the first RXRα/β- selective (or RXRα/β-dual) agonist. Being potent, less lipophilic, and having RXR subtype-selective activity, NEt-3IP (7a) is expected to become a new drug candidate and to be a useful biological tool for clarifying each RXR subtype function.
| Original language | English |
|---|---|
| Pages (from-to) | 780-787 |
| Number of pages | 8 |
| Journal | ChemMedChem |
| Volume | 3 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - May 19 2008 |
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Keywords
- Cell differentiation
- Dual agonist
- RXR agonists
- Subtype selective
- Synergistic effect
ASJC Scopus subject areas
- Pharmacology, Toxicology and Pharmaceutics(all)
- Organic Chemistry
- Molecular Medicine
Cite this
The first potent subtype-selective retinoid X receptor (RXR) agonist possessing a 3-isopropoxy-4-isopropylphenylamino moiety, NEt-3IP (RXRα/β-dual agonist). / Takamatsu, Kayo; Takano, Atsushi; Yakushiji, Nobumasa; Morohashi, Kazunori; Morishita, Kenichi; Matsuura, Nobuyasu; Makishima, Makoto; Tai, Akihiro; Sasaki, Kenji; Kakuta, Hiroki.
In: ChemMedChem, Vol. 3, No. 5, 19.05.2008, p. 780-787.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The first potent subtype-selective retinoid X receptor (RXR) agonist possessing a 3-isopropoxy-4-isopropylphenylamino moiety, NEt-3IP (RXRα/β-dual agonist)
AU - Takamatsu, Kayo
AU - Takano, Atsushi
AU - Yakushiji, Nobumasa
AU - Morohashi, Kazunori
AU - Morishita, Kenichi
AU - Matsuura, Nobuyasu
AU - Makishima, Makoto
AU - Tai, Akihiro
AU - Sasaki, Kenji
AU - Kakuta, Hiroki
PY - 2008/5/19
Y1 - 2008/5/19
N2 - 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 RXRα-preferential agonist 4-[N-methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydro-2-naphthyl)amino]benzoic acid (6a). 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 branchedalkoxy groups, 6-[N-ethyl-N-(3-isopropoxy-4-isopropylphenyl) amino]nicotinic acid(NEt-3 IP: 7a) and6-[ N-ethyl-N-(3-isobutoxy-4- isopropylphenyl)amino]nicotinic acid (NEt-3IB : 7c), showed RXR agonistic activity as potent as, or more potent than, the activities of representative RXR agonists. Moreover, NEt-3IP (7a) was found to be the first RXRα/β- selective (or RXRα/β-dual) agonist. Being potent, less lipophilic, and having RXR subtype-selective activity, NEt-3IP (7a) is expected to become a new drug candidate and to be a useful biological tool for clarifying each RXR subtype function.
AB - 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 RXRα-preferential agonist 4-[N-methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydro-2-naphthyl)amino]benzoic acid (6a). 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 branchedalkoxy groups, 6-[N-ethyl-N-(3-isopropoxy-4-isopropylphenyl) amino]nicotinic acid(NEt-3 IP: 7a) and6-[ N-ethyl-N-(3-isobutoxy-4- isopropylphenyl)amino]nicotinic acid (NEt-3IB : 7c), showed RXR agonistic activity as potent as, or more potent than, the activities of representative RXR agonists. Moreover, NEt-3IP (7a) was found to be the first RXRα/β- selective (or RXRα/β-dual) agonist. Being potent, less lipophilic, and having RXR subtype-selective activity, NEt-3IP (7a) is expected to become a new drug candidate and to be a useful biological tool for clarifying each RXR subtype function.
KW - Cell differentiation
KW - Dual agonist
KW - RXR agonists
KW - Subtype selective
KW - Synergistic effect
UR - http://www.scopus.com/inward/record.url?scp=47649097615&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=47649097615&partnerID=8YFLogxK
U2 - 10.1002/cmdc.200700313
DO - 10.1002/cmdc.200700313
M3 - Article
C2 - 18297677
AN - SCOPUS:47649097615
VL - 3
SP - 780
EP - 787
JO - ChemMedChem
JF - ChemMedChem
SN - 1860-7179
IS - 5
ER -