Dainippon Sumitomo Pharma Co., Ltd, Enoki 33-94, Suita, Osaka 564-0053, Japan.
Bioorg Med Chem. 2012 Sep 15;20(18):5568-82. doi: 10.1016/j.bmc.2012.07.023. Epub 2012 Jul 23.
Selective 18 kDa translocator protein (TSPO) ligands are expected to be therapeutic agents with a wide spectrum of action on psychiatric disorders and fewer side effects. We designed novel benzoxazolone derivatives and examined the structure-activity relationship (SAR) of a series of compounds with various substituents at the amide part and C-5 position. Although a number of the synthesized compounds showed high TSPO binding affinity, these compounds had poor drug-like properties. Further optimization of pharmacokinetic properties of these compounds led to discovery of compound 74, which exhibited anxiolytic effect in the rat Vogel conflict model.
选择性 18 kDa 转位蛋白（TSPO）配体有望成为治疗精神疾病的广谱药物，副作用更少。我们设计了新型苯并恶唑酮衍生物，并研究了一系列酰胺部分和 C-5 位具有不同取代基的化合物的结构-活性关系（SAR）。虽然许多合成的化合物表现出对 TSPO 的高结合亲和力，但这些化合物的类药性较差。进一步优化这些化合物的药代动力学性质导致了化合物 74 的发现，该化合物在大鼠 Vogel 冲突模型中表现出抗焦虑作用。
