VG081821: A ZM241385-Like A2A Receptor Antagonist With Significant Improvement in Pharmacokinetics

IF 4.2 4区医学 Q2 CHEMISTRY, MEDICINAL

Drug Development Research Pub Date : 2025-08-01 DOI:10.1002/ddr.70133

Sanxing Sun, Chongbo Hu, Jinqi Ye, Tingting Pan, Yanfen Jin, Tan Qin, Zhengshu Chen, Long Zhao

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Abstract

ZM241385 is a potent, selective A_2A receptor antagonist/inverse agonist, and has been one of the most widely used tool compounds in studies exploring the role of A_2A receptors in various conditions or probing relevant biology. However, its rapid metabolism and poor pharmacokinetic properties hindered its therapeutic use. We addressed this limitation by modifying the 4-hydroxy group on its phenyl ring, which led to the invention of VG081821. It was hypothesized that the structural modification would allow VG081821 to interact with adenosine receptors in more or less the same way. As a result, VG081821 possesses similar binding affinities and antagonistic/inverse agonistic effects on the A_2A receptor. Crucially, it possesses significantly improved metabolic stability and pharmacokinetic properties. In-vitro and in-vivo studies demonstrated VG081821's lower intrinsic clearance and superior pharmacokinetic profile compared to ZM241385. Given that more and more studies indicate that blocking A_2A receptors has multiple beneficial effects, VG081821 may have the real potential to become a clinically valuable multi-indication therapeutic agent.

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VG081821：具有显著改善药代动力学的zm241385样A2A受体拮抗剂

ZM241385是一种有效的、选择性的A2A受体拮抗剂/逆激动剂，是探索A2A受体在各种情况下的作用或探索相关生物学研究中使用最广泛的工具化合物之一。然而，其快速代谢和较差的药代动力学特性阻碍了其治疗应用。我们通过修改其苯基环上的4羟基来解决这一限制，从而发明了VG081821。据推测，这种结构修饰将允许VG081821以或多或少相同的方式与腺苷受体相互作用。因此，VG081821对A2A受体具有相似的结合亲和力和拮抗/逆激动作用。至关重要的是，它具有显著改善的代谢稳定性和药代动力学性质。体外和体内研究表明，与ZM241385相比，VG081821具有更低的内在清除率和更好的药代动力学特征。鉴于越来越多的研究表明阻断A2A受体具有多种有益作用，VG081821可能真正有潜力成为临床有价值的多适应症治疗剂。

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来源期刊

Drug Development Research 医学-药学

CiteScore

6.40

自引率

2.60%

发文量

104

审稿时长

6-12 weeks

期刊介绍： Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.