Bio-organic Laboratory, Department of Chemistry, University of Delhi, Delhi, 110 007, India.
Laboratory of Organic Chemistry, Department of Pharmacology and Therapeutical Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona Science Park, Baldiri Reixac 10-12, 08028, Barcelona, Spain.
Mol Divers. 2017 Aug;21(3):533-546. doi: 10.1007/s11030-017-9738-7. Epub 2017 Apr 25.
1,4-Dihydropyridines are well-known calcium channel blockers, but variations in the substituents attached to the ring have resulted in their role reversal making them calcium channel activators in some cases. We describe the microwave-assisted eco-friendly approach for the synthesis of pyranopyrazole-1,4-dihydropyridines, a new class of 1,4-DHPs, under solvent-free conditions in good yield, and screen them for various in silico, in vitro and in vivo activities. The in vivo experimentation results show that the compounds possess positive inotropic effect, and the docking results validate their good binding with calcium channels. Compounds 7c, 7g and 7i appear to be the most effective positive inotropes, even at low doses, and bind with the calcium channels even more strongly than Bay K 8644, a well-known calcium channel activator. The chronotropic effect for the new compounds was also studied. The target and off-target affinity profiling supported the in vivo results and revealed that the hybridized pyranopyrazole dihydropyridine scaffold has delivered new moderate hits, to be optimized, for the cytochrome P450 3A4 enzymes, opening avenues for combined pharmacological activity through standard structural modification.
1,4-二氢吡啶是众所周知的钙通道阻滞剂，但连接在环上的取代基的变化导致它们在某些情况下成为钙通道激活剂。我们描述了在无溶剂条件下微波辅助的环保方法合成吡喃并吡唑-1,4-二氢吡啶，这是一类新的 1,4-DHPs，在良好的产率下进行筛选，并对其进行各种计算机、体外和体内活性测试。体内实验结果表明，这些化合物具有正性肌力作用，对接结果验证了它们与钙通道的良好结合。化合物 7c、7g 和 7i 似乎是最有效的正性变力剂，即使在低剂量下，它们与钙通道的结合也比众所周知的钙通道激活剂 Bay K 8644 更强。新化合物的变时作用也进行了研究。靶标和非靶标亲和力分析支持体内结果，并表明杂交吡喃并吡唑二氢吡啶支架为细胞色素 P450 3A4 酶提供了新的中等亲和力的命中化合物，通过标准结构修饰为联合药理学活性开辟了途径。
