3H-Imidazo[4,5-b]pyridine-6-carboxylic acid derivatives as rexinoids with reduced teratogenicity.,Bioorganic & Medicinal Chemistry Letters

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3H-Imidazo[4,5-b]pyridine-6-carboxylic acid derivatives as rexinoids with reduced teratogenicity.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2019-05-28 , DOI: 10.1016/j.bmcl.2019.05.050
Yuta Takamura ₁ , Manami Takahashi ₁ , Midori Nishii ₂ , Osamu Shibahara ₁ , Masaki Watanabe ₁ , Michiko Fujihara ₂ , Hiroki Kakuta ₁

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Several retinoid X receptor (RXR) ligands (rexinoids), such as bexarotene (1), exhibit teratogenicity, which is a serious impediment to their clinical application. We considered that rexinoids with a lower level of maximal RXR transcription activation (i.e., partial agonists) and lower lipid solubility might show weaker adverse side effects. Based on this idea, we modified our previously reported pentamethyltetralin-type RXR partial agonists 5 and 6 to reduce their lipophilicity. Here, we report a new RXR partial agonist, 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (8, CATF-PMN), which showed greatly reduced teratogenicity in zebrafish embryos.

中文翻译：

3H-咪唑并[4,5-b]吡啶-6-羧酸衍生物，类视黄醇，致畸性降低。

几种类维生素X受体（RXR）配体（类维生素），例如贝沙罗汀（1），具有致畸性，严重阻碍了其临床应用。我们认为具有最高RXR转录激活水平较低（即部分激动剂）和较低脂质溶解度的类维生素可能显示出较弱的不良副作用。基于这个想法，我们修改了我们先前报道的五甲基四氢萘型RXR部分激动剂5和6，以降低它们的亲脂性。在这里，我们报告了一种新的RXR部分激动剂，3-（3,5,5,8,8-五甲基-5,6,7,8-四氢萘-2-基）-2-（三氟甲基）-3H-咪唑[ 4,5-b]吡啶-6-羧酸（8，CATF-PMN），在斑马鱼胚胎中显示出大大降低的致畸性。

更新日期：2019-05-28

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