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Development of a Potent and Selective G2A (GPR132) Agonist
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-06-25 , DOI: 10.1021/acs.jmedchem.3c02164
Victor Hernandez-Olmos 1, 2 , Jan Heering 1, 2 , Beatrice Marinescu 3 , Tina Schermeng 4 , Vladimir V Ivanov 5 , Yurii S Moroz 6, 7 , Sheila Nevermann 1 , Marius Mathes 3 , Johanna H M Ehrler 3 , Mohamad Wessam Alnouri 8 , Markus Wolf 9 , Alicia S Haydo 10 , Tessa Schmachtel 10 , Andrea Zaliani 9 , Georg Höfner 11 , Astrid Kaiser 3 , Manfred Schubert-Zsilavecz 3 , Annette G Beck-Sickinger 4 , Stefan Offermanns 8, 12 , Philipp Gribbon 9 , Michael A Rieger 9, 13, 14, 15 , Daniel Merk 11 , Marco Sisignano 16 , Dieter Steinhilber 1, 2, 3 , Ewgenij Proschak 1, 2, 3
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-06-25 , DOI: 10.1021/acs.jmedchem.3c02164
Victor Hernandez-Olmos 1, 2 , Jan Heering 1, 2 , Beatrice Marinescu 3 , Tina Schermeng 4 , Vladimir V Ivanov 5 , Yurii S Moroz 6, 7 , Sheila Nevermann 1 , Marius Mathes 3 , Johanna H M Ehrler 3 , Mohamad Wessam Alnouri 8 , Markus Wolf 9 , Alicia S Haydo 10 , Tessa Schmachtel 10 , Andrea Zaliani 9 , Georg Höfner 11 , Astrid Kaiser 3 , Manfred Schubert-Zsilavecz 3 , Annette G Beck-Sickinger 4 , Stefan Offermanns 8, 12 , Philipp Gribbon 9 , Michael A Rieger 9, 13, 14, 15 , Daniel Merk 11 , Marco Sisignano 16 , Dieter Steinhilber 1, 2, 3 , Ewgenij Proschak 1, 2, 3
Affiliation
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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.
中文翻译:
强效选择性 G2A (GPR132) 激动剂的开发
G 蛋白偶联受体 G2A 被认为是开发神经性疼痛、急性髓性白血病和炎症新疗法的有希望的靶点。然而,仍然缺乏有效的、选择性的、类药物的G2A激动剂来用作化学工具或作为药物开发的起始物质。在这项工作中,我们展示了一种新的有效、选择性 G2A 激动剂支架的发现和结构-活性关系阐明。系统优化导致 (3-(吡啶-3-基甲氧基)苯甲酰基) -d-苯丙氨酸 (T-10418) 表现出比参考和天然配体 9-HODE 更高的效力,并且在 G 蛋白偶联受体中具有高选择性。凭借其良好的活性、清晰的选择性、优异的溶解度和高代谢稳定性,T-10418 有资格作为研究 G2A 激活效应的药理学工具。
更新日期:2024-06-25
中文翻译:
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强效选择性 G2A (GPR132) 激动剂的开发
G 蛋白偶联受体 G2A 被认为是开发神经性疼痛、急性髓性白血病和炎症新疗法的有希望的靶点。然而,仍然缺乏有效的、选择性的、类药物的G2A激动剂来用作化学工具或作为药物开发的起始物质。在这项工作中,我们展示了一种新的有效、选择性 G2A 激动剂支架的发现和结构-活性关系阐明。系统优化导致 (3-(吡啶-3-基甲氧基)苯甲酰基) -d-苯丙氨酸 (T-10418) 表现出比参考和天然配体 9-HODE 更高的效力,并且在 G 蛋白偶联受体中具有高选择性。凭借其良好的活性、清晰的选择性、优异的溶解度和高代谢稳定性,T-10418 有资格作为研究 G2A 激活效应的药理学工具。