Discovery of Gut-Targeted GPR40 Agonist K-757 and GPR119 Agonist K-833, a Combination Treatment for Metabolic Disorders

Bariatric surgery provides long-term and robust weight loss in most patients. One leading hypothesis for this profound efficacy focuses on the increased activation of gut enteroendocrine cells (EECs), resulting in enhanced secretion of satiety hormones. We describe herein an approach using a combination of gut-targeted small molecules to stimulate intestinal nutrient receptors and mirror some of the hormone effects of bariatric surgery. In preclinical studies, administration of GPR40 agonist K-757 in combination with GPR119 agonist K-833 resulted in robust increases in the level of circulating hormones. In initial clinical studies, pharmacokinetics and pharmacodynamics for each molecule were characterized and largely recapitulated the effects of the individual compounds in mice.

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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2025-07-24
DOI
https://doi.org/10.1021/acs.jmedchem.5c01030
Citations
3
Primary Topic
Diabetes Treatment and Management
Type
article
Field-Weighted Citation Impact
3.88
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article

Discovery of Gut-Targeted GPR40 Agonist K-757 and GPR119 Agonist K-833, a Combination Treatment for Metabolic Disorders

Robert Saklatvala, Matthew J. Consolati, Daniel Kosinski, Iyassu K. Sebhat et al.
3 citations
Journal of Medicinal Chemistry
Diabetes Treatment and Management
3.88
article

Discovery of Gut-Targeted GPR40 Agonist K-757 and GPR119 Agonist K-833, a Combination Treatment for Metabolic Disorders

Robert Saklatvala, Matthew J. Consolati, Daniel Kosinski, Iyassu K. Sebhat, Christopher R. Moyes, Monika J. M. Murphy, Ann E. Weber, Robert P. J. Barretto, Jennifer Talaty, Shuwen He, Richard A. Tschirret-Guth, Simon Mathieu, Ani Galstian, Giuseppe Terracina, Eyal Vardy, Gregory D. Rak, Yunhong Zhang, Shuqin Zheng, Michael R. Luzung, Macrina T. Francisco, Xiaodong Yang, Annemarie Vance, Brett Lauring, Jiajun Liu, Bryan Chan, Shirly Pinto, S.L. Lehman, Gregory Poterewicz
article en
3 citations

Abstract

Bariatric surgery provides long-term and robust weight loss in most patients. One leading hypothesis for this profound efficacy focuses on the increased activation of gut enteroendocrine cells (EECs), resulting in enhanced secretion of satiety hormones. We describe herein an approach using a combination of gut-targeted small molecules to stimulate intestinal nutrient receptors and mirror some of the hormone effects of bariatric surgery. In preclinical studies, administration of GPR40 agonist K-757 in combination with GPR119 agonist K-833 resulted in robust increases in the level of circulating hormones. In initial clinical studies, pharmacokinetics and pharmacodynamics for each molecule were characterized and largely recapitulated the effects of the individual compounds in mice.

Journal of Medicinal ChemistryVol. 68(15)
Kallyope (United States) (US)
Good health and well-being
Openalex Percentile: Top 6%
Diabetes Treatment and Management
3.88
DOISourceOpenAlex
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