Structure-based design of potent retinoid X receptor α agonists
Structure-based design of potent retinoid X receptor α agonists
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DOI：
10.1021/jm030565g
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发表时间：
2004-04-08
影响因子：
7.3
通讯作者：
Croom, D
中科院分区：
文献类型：
--
作者：
Haffner, CD;Lenhard, JM;Croom, D
通过基于结构的设计方法合成了一系列对RXR α显示出有效激动剂活性的四氢苯并呋喃基和四氢苯并噻吩基丙烯酸。在所研究的化合物中，46 a、B不仅显示出非常好的针对RXR α（Ki = 6 nM）的效力，而且还发现相对于RAR α（Ki> 1000 nM）的选择性大于167倍。该化合物在基于细胞的瞬时转染测定中表现为完全激动剂（EC 50 = 3 nM）。通过手性色谱法分离两个对映体，发现46 b的效力比46 a高40倍。有趣的是，共结晶。46 a，B与RXR α蛋白的结合产生配体结构，由此在结合口袋中发现（S）-对映体。在db/db小鼠或ZDF大鼠中经口给予46 a、B显示出显著的降糖作用和肝脏质量增加。db/db小鼠的甘油三酯显著降低，但ZDF大鼠的甘油三酯升高。在ZDF大鼠中观察到非酯化游离脂肪酸的剂量依赖性降低，但在db/db小鼠中未观察到。这些差异表明RXR激动剂对脂质代谢的种属特异性作用。
A series of tetrahydrobenzofuranyl and tetrahydrobenzothienyl propenoic acids that showed potent agonist activity against RXRalpha were synthesized via a structure-based design approach. Among the compounds studied, 46a,b showed not only very good potency against RXRalpha (K-i = 6 nM) but was also found to be greater than 167-fold selective vs RARalpha (K-i > 1000 nM). This compound profiled out as a full agonist in a cell-based transient transfection assay (EC50 = 3 nM). The two antipodes were separated via chiral chromatography, and 46b was found to be 40-fold more potent than 46a. Interestingly, cocrystallization. of 46a,b with the RXRalpha protein generated a liganded structure whereby the (S)-antipode was found in the binding pocket. Given orally in db/db mice or ZDF rats, 46a,b showed a significant glucose-lowering effect and an increase in liver mass. Triglycerides decreased significantly in db/db mice but increased in the ZDF rats. A dose-dependent decrease of nonesterified free fatty acids was seen in ZDF rats but not in db/db mice. These differences indicate a species specific effect of RXR agonists on lipid metabolism.