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Papers of the Week

Papers: 22 Jun 2024 - 28 Jun 2024

2024 Jun 25

J Med Chem


Development of a Potent and Selective G2A (GPR132) Agonist.


Hernandez-Olmos V, Heering J, Marinescu B, Schermeng T, Ivanov VV, Moroz YS, Nevermann S, Mathes M, Ehrler JHM, Alnouri MW, Wolf M, Haydo AS, Schmachtel T, Zaliani A, Höfner G, Kaiser A, Schubert-Zsilavecz M, Beck-Sickinger AG, Offermanns S, Gribbon P, Rieger MA, 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)–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.