Discovery of N-Arylsulfonyl-Indole-2-Carboxamide Derivatives as Potent, Selective, and Orally Bioavailable Fructose-1,6-Bisphosphatase Inhibitors-Design, Synthesis, In Vivo Glucose Lowering Effects, and X-ray Crystal Complex Analysis.,Journal of Medicinal Chemistry

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Discovery of N-Arylsulfonyl-Indole-2-Carboxamide Derivatives as Potent, Selective, and Orally Bioavailable Fructose-1,6-Bisphosphatase Inhibitors-Design, Synthesis, In Vivo Glucose Lowering Effects, and X-ray Crystal Complex Analysis.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-08-21 , DOI: 10.1021/acs.jmedchem.0c00726
Jie Zhou ₁ , Jianbo Bie ₁ , Xiaoyu Wang ₁ , Quan Liu ₂ , Rongcui Li ₂ , Hualong Chen ₁ , Jinping Hu ₃ , Hui Cao ₂ , Wenming Ji ₂ , Yan Li ₃ , Shuainan Liu ₂ , Zhufang Shen ₂ , Bailing Xu ₁

Affiliation

Liver fructose-1,6-bisphosphatase (FBPase) is a key enzyme in the gluconeogenesis pathway. Inhibiting FBPase activity represents a potential treatment for type 2 diabetes mellitus. A series of novel N-arylsulfonyl-4-arylamino-indole-2-carboxamide derivatives have been disclosed as FBPase inhibitors. Through extensive structure–activity relationship investigations, a promising candidate molecule Cpd118 [sodium (7-chloro-4-((3-methoxyphenyl)amino)-1-methyl-1H-indole-2-carbonyl] [(4-methoxyphenyl)sulfonyl)amide] has been identified with high inhibitory activity against human liver FBPase (IC₅₀, 0.029 ± 0.006 μM) and high selectivity relative to the other six AMP-binding enzymes. Importantly, Cpd118 produced significant glucose-lowering effects on both type 2 diabetic KKAy mice and ZDF rats as demonstrated by substantial reductions in the fasting and postprandial blood glucose levels, as well as the HbA1c level. Furthermore, Cpd118 elicited a favorable pharmacokinetic profile with an oral bioavailability of 99.1%. Moreover, the X-ray crystal structure of the Cpd118–FBPase complex was resolved, which revealed a unique binding mode and provided a structural basis for its high potency and selectivity.

中文翻译：

发现作为有效的，选择性的和口服生物利用的果糖1,6,6-双磷酸酶抑制剂的N-芳基磺酰基-吲哚-2-羧酰胺衍生物-设计，合成，体内葡萄糖降低作用和X射线晶体复合物分析。

肝果糖-1,6-双磷酸酶（FBPase）是糖异生途径中的关键酶。抑制FBPase活性代表2型糖尿病的潜在治疗方法。已经公开了一系列新颖的N-芳基磺酰基-4-芳基氨基-吲哚-2-羧酰胺衍生物作为FBPase抑制剂。通过广泛的结构-活性关系研究，一个有前途的候选分子Cpd118 [（7-氯-4-（（3-甲氧基苯基）氨基）-1-甲基-1 H-吲哚-2-羰基钠] [（4-甲氧基苯基）相对于其他六种AMP结合酶，已鉴定出对人肝FBPase的抑制活性高（IC _50为0.029±0.006μM），并且具有较高的选择性。重要的是，Cpd118空腹和餐后血糖水平以及HbA1c水平明显降低，证明2型糖尿病KKAy小鼠和ZDF大鼠均具有明显的降糖作用。此外，Cpd118引起了良好的药代动力学特征，口服生物利用度为99.1％。此外，解析了Cpd118 -FBPase复合物的X射线晶体结构，揭示了独特的结合模式，并为其高效力和选择性提供了结构基础。

更新日期：2020-09-24

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