Pharmaceutical Sciences Department, Feik School of Pharmacy, University of the Incarnate Word, San Antonio, TX 78209, USA.
Department of Physics and Astronomy and Neuroscience Program, Trinity University, San Antonio, TX 78212, USA.
Molecules. 2023 Mar 2;28(5):2319. doi: 10.3390/molecules28052319.
In search of synthetically accessible open-ring analogs of PD144418 or 5-(1-propyl-1,2,5,6-tetrahydropyridin-3-yl)-3-(p-tolyl)isoxazole, a highly potent sigma-1 receptor (σ1R) ligand, we herein report the design and synthesis of sixteen arylated acyl urea derivatives. Design aspects included modeling the target compounds for drug-likeness, docking at σ1R crystal structure 5HK1, and contrasting the lower energy molecular conformers with that of the receptor-embedded PD144418-a molecule we opined that our compounds could mimic pharmacologically. Synthesis of our acyl urea target compounds was achieved in two facile steps which involved first generating the -(phenoxycarbonyl) benzamide intermediate and then coupling it with the appropriate amines weakly to strongly nucleophilic amines. Two potential leads (compounds and , with respective in vitro σ1R binding affinities of 2.18 and 9.54 μM) emerged from this series. These leads will undergo further structure optimization with the ultimate goal of developing novel σ1R ligands for testing in neurodegeneration models of Alzheimer's disease (AD).
为了寻找 PD144418 或 5-(1-丙基-1,2,5,6-四氢吡啶-3-基)-3-(对甲苯基)异噁唑（一种高效的 sigma-1 受体（σ1R）配体）的具有合成可及性的开环类似物，我们设计并合成了十六个芳基酰基脲衍生物。设计方面包括对目标化合物进行药物相似性建模、在 σ1R 晶体结构 5HK1 上进行对接，以及对比受体嵌入的 PD144418（我们认为我们的化合物可以在药理学上模拟的分子）的较低能量分子构象。我们的酰基脲目标化合物的合成通过两步简便的步骤实现，首先生成 -（苯氧基羰基）苯甲酰胺中间体，然后将其与适当的胺弱至强亲核胺进行偶联。从该系列中出现了两个潜在的先导化合物（化合物 和 ，其各自的体外 σ1R 结合亲和力分别为 2.18 和 9.54 μM）。这些先导化合物将进一步进行结构优化，最终目标是开发用于测试阿尔茨海默病（AD）神经退行性模型的新型 σ1R 配体。
