Design and discovery of 2-(4-(1H-tetrazol-5-yl)-1H-pyrazol-1-yl)-4-(4-phenyl)thiazole derivatives as cardiotonic agents via inhibition of PDE3.
作者： Li-Min Duan , Hong-Ying Yu , Yan-Long Li , Chun-Juan Jia
DOI: 10.1016/J.BMC.2015.08.002
关键词: Stereochemistry 、 Docking (molecular) 、 IC50 、 Mechanism of action 、 Chemistry 、 Active site 、 Vesnarinone 、 Thiazole 、 Chronotropic 、 Phosphodiesterase 3
摘要: 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 PDE3B. In PDE3 assay, entire set targeted analogs showed considerable inhibition (IC50=0.24 ± 0.06-16.42 0.14 μM) over PDE3B (IC50=2.34 0.13-28.02 0.03 μM). Among the compound 6d exhibited most potent with IC50=0.24 0.06 μM than 0.13 This was further subjected evaluation cardiotonic (contractile chronotropic effects) in comparison Vesnarinone. Results that, it selectively modulates force contraction (63%± 5) rather frequency rate (23% 2) at 100 μM. Docking study above also carried out active site protein model to give proof mechanism action designed inhibitor. Further, sub-acute toxicity experiment Swiss-albino mice, found be non-toxic up 100mg/kg dose 28days.
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