title: 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.
abstract: 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.
authors: Department of Geriatric, DaQing Oil Field General Hospital, Da Qing, Heilongjiang 16300, China.
authors: Li-Min
authors: LM
authors: Duan
authors: Department of Cardiology, DaQing Oil Field General Hospital, Da Qing, Heilongjiang 163001, China.
authors: Hong-Ying
authors: HY
authors: Yu
authors: Department of Internal Medicine, The People's Hospital of Shouguang, Shouguang 262700, China.
authors: Yan-Long
authors: YL
authors: Li
authors: Department of Internal Medicine, The People's Hospital of Shouguang, Shouguang 262700, China.
authors: Chun-Juan
authors: CJ
authors: Jia
mesh_terms: D000818:Animals; D001665:Binding Sites; D002316:Cardiotonic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D058987:Phosphodiesterase 3 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D018675:Toxicity Tests
chemical_list: C000608204:2-(4-(1H-Tetrazol-5-yl)-1H-pyrazol-1-yl)-4-(3-fluorophenyl)thiazole; D002316:Cardiotonic Agents; D058987:Phosphodiesterase 3 Inhibitors; D011720:Pyrazoles; D013844:Thiazoles; C031280:pyrazole; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517287:PDE3A protein, human; C517291:PDE3B protein, human
keywords: Cardiotonic; Docking; PDE3; Synthesis; Toxicity study