Knight Rebecca, Kilpatrick Laura E, Hill Stephen J, Stocks Michael J
Division of Biomolecular Sciences and Medicinal Chemistry, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, U.K.
Centre of Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, The Midlands NG7 2UH, U.K.
ACS Med Chem Lett. 2024 Jun 12;15(7):1127-1135. doi: 10.1021/acsmedchemlett.4c00211. eCollection 2024 Jul 11.
The P2Y receptor (P2YR) is a target for diseases including cancer, idiopathic pulmonary fibrosis, and atherosclerosis. However, there are insufficient P2YR antagonists available for validating P2YR function and future drug development. Evaluation of how ()-5-(7-chloro-2-((2-ethoxyethyl)amino)-4-benzo[5,6]cyclohepta[1,2-]thiazol-4-yl)-1-methyl-4-thioxo-3,4-dihydropyrimidin-2(1)-one, a previously published thiazole-based analogue of AR-C118925, binds in a P2YR homology model was used to design new P2YR antagonist scaffolds. One P2YR antagonist scaffold retained millimolar affinity for the P2YR and upon further functionalization with terminal carboxylic acid groups affinity was improved over 100-fold. This functionalized P2YR antagonist scaffold was employed to develop new chemotype P2YR fluorescent ligands, that were attainable in a convergent five-step synthesis. One of these fluorescent ligands demonstrated micromolar affinity (p = 6.02 ± 0.12, = 5) for the P2YR in isolated cell membranes and distinct pharmacology from an existing P2YR fluorescent antagonist, suggesting it may occupy a different binding site on the P2YR.
P2Y受体（P2YR）是包括癌症、特发性肺纤维化和动脉粥样硬化等疾病的治疗靶点。然而，目前可用于验证P2YR功能和未来药物开发的P2YR拮抗剂不足。对()-5-(7-氯-2-((2-乙氧基乙基)氨基)-4-苯并[5,6]环庚并[1,2-]噻唑-4-基)-1-甲基-4-硫代-3,4-二氢嘧啶-2(1)-酮（一种先前发表的基于噻唑的AR-C118925类似物）在P2YR同源模型中的结合方式进行评估，以此来设计新的P2YR拮抗剂支架。一种P2YR拮抗剂支架对P2YR保留了毫摩尔级亲和力，在用末端羧酸基团进一步功能化后，亲和力提高了100倍以上。这种功能化的P2YR拮抗剂支架被用于开发新的化学型P2YR荧光配体，这些配体可通过五步汇聚合成获得。其中一种荧光配体在分离的细胞膜中对P2YR表现出微摩尔级亲和力（p = 6.02 ± 0.12， = 5），且与现有的P2YR荧光拮抗剂具有不同的药理学特性，这表明它可能占据P2YR上不同的结合位点。
