The initial focus on characterizing novel pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives as DPP-4 inhibitors, led to a potent and selective inhibitor compound b2. This ligand exhibits potent in vitro DPP-4 inhibitory activity (IC₅₀: 80 nM), while maintaining other key cellular parameters such as high selectivity, low cytotoxicity and good cell viability. Subsequent optimization of b2 based on docking analysis and structure-based drug design knowledge resulted in d1. Compound d1 has nearly 2-fold increase of inhibitory activity (IC₅₀: 49 nM) and over 1000-fold selectivity against DPP-8 and DPP-9. Further in vivo IPGTT assays showed that compound b2 effectively reduce glucose excursion by 34% at the dose of 10 mg/kg in diabetic mice. Herein we report the optimization and design of a potent and highly selective series of pyrazolo[1,5-a]pyrimidin-7(4H)-one DPP-4 inhibitors.

最初集中于表征新型吡唑并[1,5 - a ]嘧啶-7（4 H）-one衍生物作为DPP-4抑制剂，导致了有效而选择性的抑制剂化合物b2的产生。该配体显示出强效的体外DPP-4抑制活性（IC ₅₀：80纳米），同时保持其它关键的细胞参数，如高选择性，低毒性和良好的细胞生存力。随后基于对接分析和基于结构的药物设计知识对b2进行优化，得出d1。化合物D1具有抑制活性的近2倍的增加（IC ₅₀：49纳米）和对着DPP-8和DPP-9 1000倍的选择性。进一步体内IPGTT分析表明，在糖尿病小鼠中，化合物b2以10 mg / kg的剂量有效降低34％的葡萄糖偏移。在这里，我们报告优化和设计的有效和高选择性系列的吡唑并[1,5 - a ]嘧啶-7（4 H）-一DPP-4抑制剂。