Design, Synthesis and SAR Studies of Novel and Potent Dipeptidyl Peptidase 4 Inhibitors,Chinese Journal of Chemistry

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Design, Synthesis and SAR Studies of Novel and Potent Dipeptidyl Peptidase 4 Inhibitors
Chinese Journal of Chemistry ( IF 5.5 ) Pub Date : 2020-09-01 , DOI: 10.1002/cjoc.202000342
Na Luo ₁ , Xiaoyu Fang ₁ , Mingbo Su ₂ , Xinwen Zhang ₂ , Dan Li ₃ , Honglin Li ₁ , Shiliang Li ₁ , Zhenjiang Zhao ₁

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Dipeptidyl peptidase 4 (DPP‐4) is a clinically validated target for the treatment of type 2 diabetes mellitus (T2DM). To discover novel and potent DPP‐4 inhibitors, three series of compounds were designed and synthesized in this study based on our previously identified novel scaffold of 2‐phenyl‐3,4‐dihydro‐2H‐benzo[f]chromen‐3‐amine. Among the designed compounds, 41d‐1 was the most potent one with an IC₅₀ value of 16.00 nM. Besides, 41d‐1 (5 mg/kg) displayed a moderate glucose tolerance capability in ICR mice. Structure‐activity‐relationship (SAR) studies were discussed in detail, which is constructive for our further optimization.

中文翻译：

新型强效二肽基肽酶4抑制剂的设计，合成和SAR研究

二肽基肽酶4（DPP-4）是经临床验证的2型糖尿病（T2DM）治疗靶标。发现新的和有效的DPP-4抑制剂，三个系列化合物的基于我们先前鉴定的新型支架设计并合成在这项研究中的2-苯基-3,4-二氢-2 ħ -苯并[ ˚F ]苯并吡喃-3-胺。在设计的化合物中，41d-1是最有效的化合物，IC ₅₀值为16.00 nM。此外，ICR小鼠的41d-1（5 mg / kg）表现出中等的葡萄糖耐量。详细讨论了结构活动关系（SAR）研究，这对我们的进一步优化具有建设性。

更新日期：2020-09-01

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