GPR34 is a rhodopsin-like class G protein-coupled receptor (GPCR) that is involved in the development and progression of several diseases. Despite its importance, effective targeting strategies are lacking. We herein report a series of (S)-3-(4-(benzyloxy)phenyl)-2-(2-phenoxyacetamido)propanoic acid derivatives as a new class of GPR34 antagonists. Structure-activity relationship (SAR) studies led to the identification of the most potent compound, 5e, which displayed an IC₅₀ value of 0.680 μM in the GloSensor cAMP assay and 0.059 μM in the Tango assay. 5e demonstrated low cytotoxicity and high selectivity in vitro, and it was able to dose-dependently inhibit Lysophosphatidylserine-induced ERK1/2 phosphorylation in CHO cells expressing GPR34. Furthermore, 5e displayed excellent efficacy in a mouse model of neuropathic pain without any apparent signs of toxicity. Collectively, this study has identified a promising compound, which shows great potential in the development of potent antagonists with a new chemical scaffold targeting GPR34.

GPR34 是一种视紫红质样 G 类蛋白偶联受体 (GPCR)，参与多种疾病的发生和进展。尽管其重要性，但仍缺乏有效的目标策略。我们在此报告了一系列( S )-3-(4-(苄氧基)苯基)-2-(2-苯氧基乙酰氨基)丙酸衍生物作为一类新的GPR34拮抗剂。构效关系 (SAR) 研究鉴定出了最有效的化合物5e，其在 GloSensor cAMP 测定中的 IC ₅₀值为 0.680 μM，在 Tango 测定中的 IC 50 值为 0.059 μM。5e在体外表现出低细胞毒性和高选择性，并且能够剂量依赖性地抑制表达GPR34的CHO细胞中溶血磷脂酰丝氨酸诱导的ERK1/2磷酸化。此外，5e在小鼠神经性疼痛模型中显示出优异的疗效，且没有任何明显的毒性迹象。总的来说，这项研究发现了一种有前途的化合物，它在开发具有针对 GPR34 的新化学支架的有效拮抗剂方面显示出巨大的潜力。