Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd. Minhang District, Shanghai, 200240, PR China; Viva Biotech Ltd. (Shanghai), No. 334 Aidisheng Rd., Pudong District, Shanghai, 201203, PR China.
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd. Minhang District, Shanghai, 200240, PR China.
Eur J Med Chem. 2020 Dec 15;208:112850. doi: 10.1016/j.ejmech.2020.112850. Epub 2020 Sep 19.
Our previous discovery of pyrazolo [1,5-a]pyrimidin-7(4H)-one scaffold-based DPP-4 inhibitors yielded two potent compounds b2 (IC = 79 nM) and d1 (IC = 49 nM) but characterized by cytotoxicity. Herein, with scaffold hopping and fragment-based drug design strategies, highly potent and selective pyrazolo [1,5-a]pyrimidine DPP-4 inhibitors were found featured by reduced or diminished cytotoxicity. Specifically, c24 (IC = 2 nM) exhibits a 25 to 40-fold increase of inhibitory activity respect to those of b2 and d1, respectively, 2-fold from Alogliptin (IC = 4 nM), and remarkable selectivity over DPP-8 and DPP-9 (>2000 fold). Further docking studies confirmed that the pyrazolo [1,5-a]pyrimidine core interacts with the S1 pocket whereas its substituted aromatic ring interacts with the sub-S1 pocket. The interactive mode in this case resembles that of Alogliptin and Trelagliptin. Further in vivo IPGTT assays in diabetic mice demonstrated that c24 effectively reduces glucose excursion by 48% at the dose of 10 mg/kg, suggesting that c24 is worthy of further development as a potent anti-diabetes agent.
我们之前发现的吡唑并[1,5-a]嘧啶-7(4H)-酮骨架 DPP-4 抑制剂产生了两种有效的化合物 b2（IC = 79 nM）和 d1（IC = 49 nM），但具有细胞毒性。在此，通过支架跳跃和基于片段的药物设计策略，发现了具有降低或减少细胞毒性的高度有效和选择性的吡唑并[1,5-a]嘧啶 DPP-4 抑制剂。具体来说，c24（IC = 2 nM）对 b2 和 d1 的抑制活性分别增加了 25 到 40 倍，比阿格列汀（IC = 4 nM）增加了 2 倍，对 DPP-8 和 DPP-9 的选择性超过 2000 倍。进一步的对接研究证实，吡唑并[1,5-a]嘧啶核心与 S1 口袋相互作用，而其取代的芳环与亚 S1 口袋相互作用。这种情况下的相互作用模式类似于阿格列汀和替格列汀。进一步在糖尿病小鼠体内 IPGTT 试验表明，c24 在 10 mg/kg 的剂量下有效降低 48%的葡萄糖波动，表明 c24 作为一种有效的抗糖尿病药物具有进一步开发的价值。
