Novel NPY2R agonist BI 1820237 provides synergistic anti-obesity efficacy when combined with the GCGR/GLP-1R dual agonist survodutide

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism Pub Date : 2025-07-05 DOI:10.1016/j.molmet.2025.102205

Robert Augustin , Anouk Oldenburger , Tamara Baader-Pagler , Tina Zimmermann , Jens Borghardt , Jacob Hecksher-Sørensen , Angela Baljuls , Wolfgang Reindl , Bartlomiej Krawczyk , Eric Martel , Albert Brennauer , Stefan Peters , Achim Grube , Lise Biehl Rudkjaer , Peter Haebel

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引用次数: 0

Abstract

Objective

Nutrient-stimulated gut hormone peptide YY3–36 (PYY3–36) selectively activates the neuropeptide Y2 receptor (NPY2R) and reduces energy intake in humans. We describe the discovery and pharmacology of the long-acting NPY2R agonist BI 1820237 and its potential bodyweight-lowering efficacy alone and in combination with the glucagon receptor (GCGR)/glucagon-like peptide-1 receptor (GLP-1R) dual agonist survodutide.

Methods & Results

BI 1820237 dose-dependently reduced food intake and gastric emptying in lean mice. Significant bodyweight reductions were not observed with BI 1820237 alone in diet-induced obese mice, however combination with survodutide led to bodyweight reduction of 22% which was significantly (p < 0.01) greater than the 17% bodyweight reduction with survodutide alone. Regression-based interaction analysis demonstrated that BI 1820237 increased the efficacy of survodutide by 265% at an ED50 of 11.7 nmol/kg over a range of dose combinations.

Conclusion

Synergistic NPY2R and GCGR/GLP-1R agonism provides an attractive mode of action for clinically relevant weight loss in patients with obesity.

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新型NPY2R激动剂BI 1820237与GCGR/GLP-1R双激动剂联合使用时具有协同抗肥胖功效。

营养刺激的肠道激素肽YY3-36 （PYY3-36）选择性地激活神经肽Y2受体（NPY2R）并减少人类的能量摄入。我们描述了长效NPY2R激动剂BI 1820237的发现和药理学，以及其单独和与胰高血糖素受体(GCGR)/胰高血糖素样肽-1受体（GLP-1R）双重激动剂survodutide联合使用的潜在减肥功效。BI 1820237剂量依赖性地减少瘦小鼠的食物摄入和胃排空。在饮食诱导的肥胖小鼠中，单独使用BI 1820237未观察到显著的体重减轻，但与生存肽联合使用可使体重减轻22%，在一系列剂量组合中显着（p50为11.7 nmol/kg）。协同NPY2R和GCGR/GLP-1R激动作用为肥胖患者的临床相关减肥提供了一种有吸引力的作用模式。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

14.50

自引率

2.50%

发文量

219

审稿时长

43 days

期刊介绍： Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction. We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.