2. Academic Validation
  3. Structural optimization of pyrazolo[1,5-a]pyrimidine derivatives as potent and highly selective DPP-4 inhibitors

Structural optimization of pyrazolo[1,5-a]pyrimidine derivatives as potent and highly selective DPP-4 inhibitors

  • Eur J Med Chem. 2020 Dec 15;208:112850. doi: 10.1016/j.ejmech.2020.112850.
Jian Shen 1,  Xinxian Deng 2,  Ran Sun 2,  Mojdeh S Tavallaie 2,  Juntao Wang 2,  Qingqing Cai 3,  Celine Lam 2,  Shuwen Lei 2,  Lei Fu 4,  Faqin Jiang 5
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Department of Pharmacy, Fudan University Affiliated Zhongshan Hospital, No. 250 Xiaomuqiao Rd. Shanghai, 200032, Xuhui District, Shanghai, PR China.
  • 4 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. Electronic address: leifu@sjtu.edu.cn.
  • 5 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. Electronic address: jfq2008@sjtu.edu.cn.
PMID: 32987315 DOI: 10.1016/j.ejmech.2020.112850
Abstract

Our previous discovery of pyrazolo [1,5-a]pyrimidin-7(4H)-one scaffold-based DPP-4 inhibitors yielded two potent compounds b2 (IC50 = 79 nM) and d1 (IC50 = 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 (IC50 = 2 nM) exhibits a 25 to 40-fold increase of inhibitory activity respect to those of b2 and d1, respectively, 2-fold from Alogliptin (IC50 = 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.

Keywords

DPP-4 inhibitor; Fragment-based drug design; Pyrazolo[1,5-a]pyrimidine derivatives; Scaffold hopping; Type 2 diabetes mellitus (T2DM).

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