Duan Li-Min, Yu Hong-Ying, Li Yan-Long, Jia Chun-Juan
Department of Geriatric, DaQing Oil Field General Hospital, Da Qing, Heilongjiang 16300, China.
Department of Cardiology, DaQing Oil Field General Hospital, Da Qing, Heilongjiang 163001, China.
Bioorg Med Chem. 2015 Sep 15;23(18):6111-7. doi: 10.1016/j.bmc.2015.08.002. Epub 2015 Aug 7.
A series of novel 2-(4-(1H-tetrazol-5-yl)-1H-pyrazol-1-yl)-4-(4-phenyl)thiazole derivatives, 6(a-o) were designed, synthesized and evaluated for inhibitory activity against human PDE3A and PDE3B. In PDE3 assay, entire set of targeted analogs showed considerable inhibition of PDE3A (IC50=0.24 ± 0.06-16.42 ± 0.14 μM) over PDE3B (IC50=2.34 ± 0.13-28.02 ± 0.03 μM). Among the synthesized derivatives, compound 6d exhibited most potent inhibition of PDE3A with IC50=0.24 ± 0.06 μM than PDE3B (IC50=2.34 ± 0.13 μM). This compound was further subjected for evaluation of cardiotonic activity (contractile and chronotropic effects) in comparison with Vesnarinone. Results showed that, it selectively modulates the force of contraction (63%± 5) rather than frequency rate (23% ± 2) at 100 μM. Docking study of above compound was also carried out in the active site of PDE3 protein model to give proof to the mechanism of action of designed inhibitor. Further, in sub-acute toxicity experiment in Swiss-albino mice, it was found to be non-toxic up to 100mg/kg dose for 28days.
设计、合成了一系列新型的2-(4-(1H-四唑-5-基)-1H-吡唑-1-基)-4-(4-苯基)噻唑衍生物6(a - o)，并对其抑制人磷酸二酯酶3A（PDE3A）和磷酸二酯酶3B（PDE3B）的活性进行了评估。在PDE3检测中，所有靶向类似物对PDE3A的抑制作用（IC50 = 0.24 ± 0.06 - 16.42 ± 0.14 μM）均显著高于PDE3B（IC50 = 2.34 ± 0.13 - 28.02 ± 0.03 μM）。在合成的衍生物中，化合物6d对PDE3A的抑制作用最强，IC50 = 0.24 ± 0.06 μM，而对PDE3B的抑制作用（IC50 = 2.34 ± 0.13 μM）较弱。将该化合物与维司力农进行比较，进一步评估其强心活性（收缩和变时作用）。结果表明，在100 μM时，它选择性地调节收缩力（63% ± 5），而不是心率（23% ± 2）。还对上述化合物在PDE3蛋白模型的活性位点进行了对接研究，以验证所设计抑制剂的作用机制。此外，在瑞士白化小鼠的亚急性毒性实验中，发现该化合物在剂量高达100mg/kg、持续28天的情况下无毒。
