Trends in GPCR drug discovery: new agents, targets and indications

Key Points We report an analysis of all drugs and agents currently in clinical trials that act via G protein-coupled receptors (GPCRs) – the most intensively studied drug target family. There are currently 475 drugs (~34% of all drugs approved by the FDA) that act on 108 unique GPCR targets. Approximately 321 agents are currently in clinical trials, of which ~20% target 66 potentially novel GPCR targets that do not currently have an approved drug. Biological drugs, allosteric modulators and biased agonists are becoming more frequent in clinical trials. The major disease indications for GPCR modulators show a shift towards diabetes, obesity and Alzheimer disease, although other central nervous system disorders are also highly represented. The 224 (56%) non-olfactory GPCRs that are yet to be explored in clinical trials have broad untapped therapeutic potential, particularly in genetic and immune system disorders. Further trends in GPCR drug discovery can be analysed in an interactive resource in the GPCRdb database. G protein-coupled receptors (GPCRs) are the most intensively studied class of drug targets. This article presents a pioneering analysis of all GPCR-targeted drugs and agents that are currently in clinical trials, and discusses the trends across molecule types, drug targets and therapeutic indications. 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 an