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J. Med. Chem. 2024, 67 (13), 10567-10588

DOI: 10.1021/acs.jmedchem.3c02164

Hernandez-Olmos V.; Heering J.; Marinescu B.; Schermeng T.; Ivanov V. V.; Moroz Y. S.; Nevermann S.; Mathes M.; Ehrler J. H. M.; Alnouri M. W.; Wolf M.; Haydo A. S.; Schmachtel T.; Zaliani A.; Hofner G.; Kaiser A.; Schubert-Zsilavecz M.; Beck-Sickinger A. G.; Offermanns S.; Gribbon P.; Rieger M. A.; Merk D.; Sisignano M.; Steinhilber D.; Proschak E.

G protein-coupled receptor G2A was postulated to be a promising target for the development of new therapeutics in neuropathic pain, acute myeloid leukemia, and inflammation. However, there is still a lack of potent, selective, and drug-like G2A agonists to be used as a chemical tool or as the starting matter for the development of drugs. In this work, we present the discovery and structure–activity relationship elucidation of a new potent and selective G2A agonist scaffold. Systematic optimization resulted in (3-(pyridin-3-ylmethoxy)benzoyl)-d-phenylalanine (T-10418) exhibiting higher potency than the reference and natural ligand 9-HODE and high selectivity among G protein-coupled receptors. With its favorable activity, a clean selectivity profile, excellent solubility, and high metabolic stability, T-10418 qualifies as a pharmacological tool to investigate the effects of G2A activation.

 

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