Hauser Alexander S, Attwood Misty M, Rask-Andersen Mathias, Schiöth Helgi B, Gloriam David E
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
Department of Neuroscience, Functional Pharmacology, University of Uppsala, 751 05 Uppsala, Sweden.
Nat Rev Drug Discov. 2017 Dec;16(12):829-842. doi: 10.1038/nrd.2017.178. Epub 2017 Oct 27.
G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, mostly due to their substantial involvement in human pathophysiology and their pharmacological tractability. Here, we report an up-to-date analysis of all GPCR drugs and agents in clinical trials, which reveals current trends across molecule types, drug targets and therapeutic indications, including showing that 475 drugs (~34% of all drugs approved by the US Food and Drug Administration (FDA)) act at 108 unique GPCRs. Approximately 321 agents are currently in clinical trials, of which ~20% target 66 potentially novel GPCR targets without an approved drug, and the number of biological drugs, allosteric modulators and biased agonists has increased. The major disease indications for GPCR modulators show a shift towards diabetes, obesity and Alzheimer disease, although several central nervous system disorders are also highly represented. The 224 (56%) non-olfactory GPCRs that have not yet been explored in clinical trials have broad untapped therapeutic potential, particularly in genetic and immune system disorders. Finally, we provide an interactive online resource to analyse and infer trends in GPCR drug discovery.
G蛋白偶联受体（GPCRs）是研究最为深入的药物靶点，主要是因为它们在人类病理生理学中发挥着重要作用，并且具有药理学可操作性。在此，我们报告了对所有处于临床试验阶段的GPCR药物和制剂的最新分析，揭示了分子类型、药物靶点和治疗适应症的当前趋势，包括显示475种药物（约占美国食品药品监督管理局（FDA）批准的所有药物的34%）作用于108个独特的GPCRs。目前约有321种制剂正在进行临床试验，其中约20%靶向66个尚无获批药物的潜在新型GPCR靶点，并且生物药物、变构调节剂和偏向激动剂的数量有所增加。GPCR调节剂的主要疾病适应症呈现出向糖尿病、肥胖症和阿尔茨海默病的转变，尽管几种中枢神经系统疾病也占比较高。224个（56%）尚未在临床试验中得到探索的非嗅觉GPCRs具有广泛的未开发治疗潜力，尤其是在遗传和免疫系统疾病方面。最后，我们提供了一个交互式在线资源，用于分析和推断GPCR药物发现的趋势。
