RXR Partial Agonist Produced by Side Chain Repositioning of Alkoxy RXR Full Agonist Retains Antitype 2 Diabetes Activity without the Adverse Effects
RXR Partial Agonist Produced by Side Chain Repositioning of Alkoxy RXR Full Agonist Retains Antitype 2 Diabetes Activity without the Adverse Effects
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DOI：
10.1021/jm501863r
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发表时间：
2015-01-22
影响因子：
7.3
通讯作者：
Kakuta, Hiroki
中科院分区：
文献类型：
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作者：
Kawata, Kohei;Morishita, Ken-ichi;Kakuta, Hiroki
我们先前报道了RXR部分激动剂CBt-PMN（1-（3，5，5，8，8-五甲基-5，6，7，8-四氢-2-萘基）-1H-苯并三唑-5-羧酸：5，EC 50 = 143 nM，E-max = 75%），其显示出有效的降糖作用，而不会引起严重的不良反应。然而，阐明RXR功效和降糖作用的结构要求仍然很重要，因为据报道，RXR允许的异二聚体如PPAR/RXR或LXR/RXR根据RXR激动剂的化学结构被不同地激活。在这项工作中，我们表明RXR部分激动剂NEt-4 IB（6-[乙基-（4-异丁氧基-3-异丙基苯基）氨基]吡啶-3-甲酸：8b，EC50 = 169 nM，E-max = 55%），可以简单地通过重新定位侧链在RXR完全激动剂NEt-3 IB的疏水部分处的（互换异丁氧基和异丙氧基）（6-[乙基-（3-异丁氧基-4-异丙基苯基）氨基]吡啶-3-甲酸：7 b，EC 50 = 19 nM）。NEt-4 IB（8b）在以10 mg/kg/天重复口服给药于小鼠时显示出抗2型糖尿病活性，而没有上述副作用，与5类似。
We previously reported RXR partial agonist CBt-PMN (1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid: 5, EC50 = 143 nM, E-max = 75%), which showed a potent glucose-lowering effect without causing serious adverse effects. However, it remains important to elucidate the structural requirements for RXR efficacy and the glucose-lowering effect because RXR-permissive heterodimers such as PPAR/RXR or LXR/RXR are reported to be activated differently depending upon the chemical structure of RXR agonists. In this work, we show that an RXR partial agonist, NEt-4IB (6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: 8b, EC50 = 169 nM, E-max = 55%), can be obtained simply by repositioning the side chains (interchanging the isobutoxy and isopropoxy groups) at the hydrophobic moiety of the RXR full agonist NEt-3IB (6-[ethyl-(3-isobutoxy-4-isopropylphenyl)amino]pyridine-3-carboxylic acid: 7b, EC50 = 19 nM). NEt-4IB (8b) showed antitype 2 diabetes activity without the above side effects upon repeated oral administration to mice at 10 mg/kg/day, similarly to 5.