Optimization of the benzamide fragment targeting the S2′ site leads to potent dipeptidyl peptidase-IV inhibitors
Optimization of the benzamide fragment targeting the S2′ site leads to potent dipeptidyl peptidase-IV inhibitors
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DOI：
10.1016/j.bioorg.2019.103366
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发表时间：
2020-01-01
影响因子：
5.1
通讯作者：
Li, Qing
中科院分区：
文献类型：
--
作者：
Deng, Xiaoyan;Wang, Na;Li, Qing
我们最近成功鉴定了基于苯甲酸的DPP-4抑制剂，这刺激了对S-2'位点DPP-4的深入构效关系（SAR）研究的进一步探索。因此，新的苯甲酰胺片段被设计为靶向S-2'位点以损害亲脂性并改善口服活性。通过在苯环上引入各种酰胺和卤素来探索SAR，鉴定出几种化合物，发挥中度至优异的DPP-4活性，其中4 '-氯取代甲基酰胺17 g显示出最强的DPP-4活性，IC 50值为1.6 nM。其活性上级优于对照品阿糖胞苷。对接研究理想地验证和解释了所获得的设计化合物的SAR。作为延续，DPP-8/9测定显示所设计的化合物对DPP-8和DPP-9表现出良好的选择性。随后的基于细胞的试验表明化合物17 g对LO 2细胞系显示出低毒性，高达100 μ M。体内评价显示化合物17 g稳健地改善正常小鼠的葡萄糖耐量。重要的是，17 g显示出合理的口服给药代动力学（PK）特征。总体而言，化合物17 g具有成为用于T2 DM治疗的安全且有效的DPP-4抑制剂的潜力。
Our recently successful identification of benzoic acid-based DPP-4 inhibitors spurs the further quest for in-depth structure-activity relationships (SAR) study in S-2' site DPP-4. Thus novel benzamide fragments were designed to target the S-2' site to compromise lipophilicity and improve oral activity. Exploring SAR by introduction of a variety of amide and halogen on benzene ring led to identification of several compounds, exerting moderated to excellent DPP-4 activities, in which 4'-chlorine substituted methyl amide 17 g showed most potent DPP-4 activity with the IC50 value of 1.6 nM. Its activity was superior to reference alogliptin. Docking study ideally verified and interpreted the obtained SAR of designed compounds. As a continuation, DPP-8/9 assays revealed the designed compounds exhibited good selectivity over DPP-8 and DPP-9. Subsequent cell-based test indicated compound 17g displayed low toxicity toward the LO2 cell line up to 100 mu M. In vivo evaluation showed compound 17g robustly improved the glucose tolerance in normal mice. Importantly, 17g exhibited reasonable pharmacokinetic (PK) profiles for oral delivery. Overall, compound 17g has the potential to a safe and efficacious DPP-4 inhibitor for T2DM treatment.