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

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

Summary: 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 e...

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Main Authors: 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
Format: Article
Language:English
Published: Elsevier 2025-09-01
Series:Molecular Metabolism
Subjects:
PYY3–36
NPY
NPY2R
BI 1820237
Survodutide
Obesity
Online Access:http://www.sciencedirect.com/science/article/pii/S2212877825001127
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Summary:Summary: 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 &amp; 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.
ISSN:2212-8778

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