基于药效团模型的设计、合成强效抗高血压药物：氧杂/噻唑并[3,2-a]嘧啶-3(2H)-酮和 1,5-二氢咪唑并[1,2-a]嘧啶-3(2H)-酮衍生物：初步试验。
Pharmacophore modeling, design, and synthesis of potent antihypertensives, oxazolo/thiazolo-[3,2-a]-pyrimidin-3(2H)-one, and 1,5-dihydroimidazo-[1,2-a]-pyrimidin-3(2H)-one derivatives: A pilot trial.
机构信息
Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences and Research, Jamia Hamdard, New Delhi 110062, India.
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Qassim 51452, Saudi Arabia.
出版信息
Bioorg Med Chem Lett. 2020 Dec 1;30(23):127604. doi: 10.1016/j.bmcl.2020.127604. Epub 2020 Oct 7.
An improved pharmacophore model, molecular properties, geometric analyses, and SAR led to synthesize oxazolo/thiazolo-[3,2-a]-pyrimidin-3(2H)-one, and 1,5-dihydroimidazo-[1,2-a]-pyrimidin-3(2H)-one derivatives exhibiting potent anti-hypertensive activity. The 6-ethoxycarbonyl-2,7-dimethyl-5-phenyl-1,5-dihydroimidazo[3,2-a]pyrimidin-3(2H)-one (4g), and 6-ethoxycarbonyl-2,7-dimethyl-5-(3-methyl-phenyl)-1,5-dihydroimidazo[3,2-a]pyrimidin-3(2H)-one (4h) showed significant reduction in mean arterial blood pressure (MABP, mm/Hg) of 79.78%, and 92.95% in 6 and 12 h durations, respectively, at 1.5 mg/kg body-weight dose, while at 3.0 mg/kg body-weight dose, the MABP reduction was achieved at 95.46%, and 92.02%, respectively, in 6 and 12 h durations, as compared to the standard drug, nifedipine.
一个改进的药效团模型、分子性质、几何分析和 SAR 导致合成了氧杂环/噻唑并-[3,2-a]-嘧啶-3(2H)-酮和 1,5-二氢咪唑并-[1,2-a]-嘧啶-3(2H)-酮衍生物，表现出很强的抗高血压活性。6-乙氧羰基-2,7-二甲基-5-苯基-1,5-二氢咪唑并[3,2-a]嘧啶-3(2H)-酮（4g）和 6-乙氧羰基-2,7-二甲基-5-(3-甲基苯基）-1,5-二氢咪唑并[3,2-a]嘧啶-3(2H)-酮（4h）在 1.5mg/kg 体重剂量下，分别在 6 和 12 小时内使平均动脉血压（MABP，mmHg）显著降低 79.78%和 92.95%，而在 3.0mg/kg 体重剂量下，MABP 降低分别达到 95.46%和 92.02%，在 6 和 12 小时内，与标准药物硝苯地平相比。
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