Hibi S, Kikuchi K, Yoshimura H, Nagai M, Tai K, Hida T
Tsukuba Basic Research Laboratories, Eisai Co., Ltd., 1-3, Tokodai 5-chome, Tsukuba-shi, Ibaraki, 300-26, Japan.
J Med Chem. 1998 Aug 13;41(17):3245-52. doi: 10.1021/jm980058c.
As part of our studies to develop novel retinoids with increased affinity and selectivity for the retinoid X receptor (RXR) subfamily, we have designed and synthesized a series of (E,E,E)-7-(1,2,3, 4-tetrahydroquinolin-6-yl)-7-alkyl-6-fluoro-3-methylhepta-2, 4, 6-trienoic acid derivatives. These tetrahydroquinolines, generated by introducing a polar N atom into the hydrophobic part of the retinoid skeleton, showed high binding affinity to RXRs. Addition of fluorine at the 6-position of the 2,4,6-trienoic acid moiety afforded compounds which elicit potent and selective transactivation of the RXRs. Compound 14b (ER-35794), which possesses an ethyl substituent at the 7-position and fluorine at the 6-position of the triene moiety, is one of the most potent and selective RXR agonists reported to date.
作为我们开发对维甲酸X受体（RXR）亚家族具有更高亲和力和选择性的新型维甲酸研究的一部分，我们设计并合成了一系列（E,E,E）-7-（1,2,3,4-四氢喹啉-6-基）-7-烷基-6-氟-3-甲基庚-2,4,6-三烯酸衍生物。通过将极性氮原子引入维甲酸骨架的疏水部分生成的这些四氢喹啉，对RXRs表现出高结合亲和力。在2,4,6-三烯酸部分的6位添加氟得到了能引发RXRs有效且选择性反式激活的化合物。化合物14b（ER-35794）在7位具有乙基取代基，在三烯部分的6位具有氟，是迄今为止报道的最有效且选择性最高的RXR激动剂之一。
