کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1393817 1501103 2016 12 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Design, synthesis and Structure–activity relationship studies of new thiazole-based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes
ترجمه فارسی عنوان
بررسی ارتباط ساختار، سنتز و ساختار فعالیت های جدید تریازول بر اساس آگونیست گیرنده های چربی آزاد مبتنی بر تیازول برای درمان دیابت نوع 2
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
چکیده انگلیسی


• 11 heterocycles were synthesized to improve the lipophilicity of TAK-875.
• The methyl group in our thiazole core occupied a crucial hydrophobic subpocket.
• The agonistic activity revealed a good correlation with the dihedral angle.
• 44 revealed lower risk of liver toxicity compared with TAK-875.
• 44 showed lower risk of hypoglycemia compared to first-line drug glibenclamide.

The free fatty acid receptor 1 (FFA1/GPR40) has attracted interest as a novel target for the treatment of type 2 diabetes. Several series of FFA1 agonists including TAK-875, the most advanced compound terminated in phase III studies due to concerns about liver toxicity, have been hampered by relatively high molecular weight and lipophilicity. Aiming to develop potent FFA1 agonists with low risk of liver toxicity by decreasing the lipophilicity, the middle phenyl of TAK-875 was replaced by 11 polar five-membered heteroaromatics. Subsequently, systematic exploration of SAR and application of molecular modeling, leads to the identification of compound 44, which was an excellent FFA1 agonist with robustly hypoglycemic effect both in normal and type 2 diabetic mice, low risks of hypoglycemia and liver toxicity even at the twice molar dose of TAK-875. Meanwhile, two important findings were noted. First, the methyl group in our thiazole series occupied a small hydrophobic subpocket which had no interactions with TAK-875. Furthermore, the agonistic activity revealed a good correlation with the dihedral angle between thiazole core and the terminal benzene ring. These results promote the understanding of ligand-binding pocket and might help to design more promising FFA1 agonists.

11 polar heteroaromatics were designed and synthesized to improve the lipophilicity and liver toxicity of TAK-875.Figure optionsDownload as PowerPoint slide

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Medicinal Chemistry - Volume 113, 4 May 2016, Pages 246–257
نویسندگان
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