School of Chemistry and Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM), School of Medicine, University of Leeds, Leeds LS2 9JT, U.K.
Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM), School of Medicine, University of Leeds, Leeds LS2 9JT, U.K.
J Med Chem. 2020 Nov 12;63(21):12213-12242. doi: 10.1021/acs.jmedchem.0c00262. Epub 2020 Jun 30.
Pathogenic thrombus formation accounts for the etiology of many serious conditions including myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism. Despite the development of numerous anticoagulants and antiplatelet agents, the mortality rate associated with these diseases remains high. In recent years, however, significant epidemiological evidence and clinical models have emerged to suggest that modulation of the glycoprotein VI (GPVI) platelet receptor could be harnessed as a novel antiplatelet strategy. As such, many peptidic agents have been described in the past decade, while more recent efforts have focused on the development of small molecule modulators. Herein the rationale for targeting GPVI is summarized and the published GPVI modulators are reviewed, with particular focus on small molecules. A qualitative pharmacophore hypothesis for small molecule ligands at GPVI is also presented.
致病血栓形成是许多严重疾病的病因，包括心肌梗死、中风、深静脉血栓形成和肺栓塞。尽管开发了许多抗凝剂和抗血小板药物，但这些疾病的死亡率仍然很高。然而，近年来，出现了大量的流行病学证据和临床模型，表明调节糖蛋白 VI（GPVI）血小板受体可以作为一种新的抗血小板策略。因此，在过去十年中描述了许多肽类药物，而最近的研究重点则放在小分子调节剂的开发上。本文总结了靶向 GPVI 的原理，并综述了已发表的 GPVI 调节剂，特别关注小分子。本文还提出了针对 GPVI 的小分子配体的定性药效团假说。
