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

Autor:	Hernandez-Olmos V; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.; Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany., Heering J; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.; Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany., Marinescu B; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Street 9, 60438 Frankfurt am Main, Germany., Schermeng T; Institute of Biochemistry, Faculty of Life Sciences, Leipzig University, Brüderstraße 34, 04103 Leipzig, Germany., Ivanov VV; Enamine Ltd, 67 Chervonotkatska Street, Kyiv 02094, Ukraine., Moroz YS; Taras Shevchenko National University of Kyiv, 64 Volodymyrska Street, Kyiv 01601, Ukraine.; Chemspace LLC, 85 Chervonotkatska Street, Kyiv 02094, Ukraine., Nevermann S; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany., Mathes M; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Street 9, 60438 Frankfurt am Main, Germany., Ehrler JHM; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Street 9, 60438 Frankfurt am Main, Germany., Alnouri MW; Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Ludwigstr. 43, 61231Bad Nauheim, Germany., Wolf M; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, Schnackenburgallee 114, 22525 Hamburg, Germany., Haydo AS; Department of Medicine, Hematology/Oncology, Goethe University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany., Schmachtel T; Department of Medicine, Hematology/Oncology, Goethe University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany., Zaliani A; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, Schnackenburgallee 114, 22525 Hamburg, Germany., Höfner G; Department of Pharmacy, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany., Kaiser A; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Street 9, 60438 Frankfurt am Main, Germany., Schubert-Zsilavecz M; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Street 9, 60438 Frankfurt am Main, Germany., Beck-Sickinger AG; Institute of Biochemistry, Faculty of Life Sciences, Leipzig University, Brüderstraße 34, 04103 Leipzig, Germany., Offermanns S; Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Ludwigstr. 43, 61231Bad Nauheim, Germany.; Center for Molecular Medicine, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany., Gribbon P; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, Schnackenburgallee 114, 22525 Hamburg, Germany., Rieger MA; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, Schnackenburgallee 114, 22525 Hamburg, Germany.; Frankfurt Cancer Institute, 60590 Frankfurt am Main, Germany.; Cardio-Pulmonary Institute (CPI), 60590 Frankfurt am Main, Germany.; German Cancer Consortium (DKTK) and German Cancer Research Institute (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany., Merk D; Department of Pharmacy, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany., Sisignano M; Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany., Steinhilber D; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.; Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Street 9, 60438 Frankfurt am Main, Germany., Proschak E; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.; Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Street 9, 60438 Frankfurt am Main, Germany.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Jul 11; Vol. 67 (13), pp. 10567-10588. Date of Electronic Publication: 2024 Jun 25.
DOI:	10.1021/acs.jmedchem.3c02164
Abstrakt:	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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu