TY - JOUR
T1 - Reduction of lipophilicity at the lipophilic domain of RXR agonists enables production of subtype preference
T2 - RXRα-preferential agonist possessing a sulfonamide moiety
AU - Takamatsu, Kayo
AU - Takano, Atsushi
AU - Yakushiji, Nobumasa
AU - Morishita, Ken Ichi
AU - Matsuura, Nobuyasu
AU - Makishima, Makoto
AU - Ali, Hamed Ismail
AU - Akaho, Eiichi
AU - Tai, Akihiro
AU - Sasaki, Kenji
AU - Kakuta, Hiroki
PY - 2008/3/14
Y1 - 2008/3/14
N2 - Retinoid X receptor agonists (RXR agonists, rexinoids) are interesting candidates for the treatment of cancers such as tamoxifen-resistant breast cancer and taxol-resistant lung cancer. However, well-known RXR agonists possess a strong lipophilic character. In addition, although RXR has three subtypes, no subtype-selective RXR agonists are known. Thus we aimed to produce less-lipophilic and subtype-selective RXR agonists. By designing sulfonamide-type RXR agonists, 4-[N-methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydro-2-naphthyl)amino]benzoic acid (8a) was found to prefer RXRα over RXRβ and RXRγ, although the potencyis less than the potencies of well-known RXR pan-agonists. Moreover, our results suggest that the reduction of lipophilicityat the hydrophobic interaction region of RXR agonists enables production of RXR subtype preference. Our finding will be useful for the creation of more potent and less-lipophilic subtype-selective RXR agonists aimed at the reduction of undesirable side effects.
AB - Retinoid X receptor agonists (RXR agonists, rexinoids) are interesting candidates for the treatment of cancers such as tamoxifen-resistant breast cancer and taxol-resistant lung cancer. However, well-known RXR agonists possess a strong lipophilic character. In addition, although RXR has three subtypes, no subtype-selective RXR agonists are known. Thus we aimed to produce less-lipophilic and subtype-selective RXR agonists. By designing sulfonamide-type RXR agonists, 4-[N-methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydro-2-naphthyl)amino]benzoic acid (8a) was found to prefer RXRα over RXRβ and RXRγ, although the potencyis less than the potencies of well-known RXR pan-agonists. Moreover, our results suggest that the reduction of lipophilicityat the hydrophobic interaction region of RXR agonists enables production of RXR subtype preference. Our finding will be useful for the creation of more potent and less-lipophilic subtype-selective RXR agonists aimed at the reduction of undesirable side effects.
KW - Docking simulations
KW - RXR agonists
KW - Subtype preference
KW - Subtype selectivity
KW - Sulfonamides
KW - Synergistic effects
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U2 - 10.1002/cmdc.200700265
DO - 10.1002/cmdc.200700265
M3 - Article
C2 - 18157857
AN - SCOPUS:48049114021
VL - 3
SP - 454
EP - 460
JO - Farmaco
JF - Farmaco
SN - 1860-7179
IS - 3
ER -