设计、合成及部分取代的二氢嘧啶类 L-/T-型钙通道阻滞活性的药理学评价。
Design, synthesis and pharmacological evaluation of some substituted dihydropyrimidines with L-/T-type calcium channel blocking activities.
机构信息
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Drug Manufacturing, Pharos University in Alexandria, Alexandria 21311, Egypt.
出版信息
Bioorg Chem. 2019 Mar;83:354-366. doi: 10.1016/j.bioorg.2018.10.054. Epub 2018 Nov 1.
New dihydropyrimidines bearing various lipophilic pharmacophores and functionalities at position 3 were designed and synthesized. The basic framework of the new compounds was designed to maintain the main structural requirements for calcium channel blocking activity of the known dihydropyridines and dihydropyrimidines calcium channel blockers. The newly synthesized compounds were evaluated as antagonists for Ca1.2 and Ca3.2 using the whole-cell patch clamp technique. Seven compounds (4b, 4c, 6c, 9, 13c, 13e and 17b) showed promising dual calcium channel blocking activity and three compounds (13b, 14b and 17a) were selective against Cav3.2. Their drug-likeness has been assessed using Molinspiration and Molsoft softwares. Their physicochemical properties and pharmacokinetic profiles recommend that they can be considered as drug-like candidates.
设计并合成了一系列在 3 位具有不同亲脂性药效团和官能团的新型二氢嘧啶。新化合物的基本结构框架旨在保持已知二氢吡啶和二氢嘧啶类钙通道阻滞剂的钙通道阻断活性的主要结构要求。使用全细胞膜片钳技术，将新合成的化合物评估为 Ca1.2 和 Ca3.2 的拮抗剂。有 7 种化合物（4b、4c、6c、9、13c、13e 和 17b）表现出有希望的双重钙通道阻断活性，有 3 种化合物（13b、14b 和 17a）对 Cav3.2 具有选择性。使用 Molinspiration 和 Molsoft 软件评估了它们的类药性。它们的物理化学性质和药代动力学特征表明，它们可以被认为是类药性候选物。
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