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Molecular Pharmacology

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CPL207280 - a novel GPR40/FFA1-specific agonist shows a favorable safety profile and exerts anti-diabetic effects in type 2 diabetic animals.

Katarzyna Bazydlo-Guzenda, Pawel Buda, Mikolaj Matloka, Mateusz Mach, Filip Stelmach, Radoslaw Dzida, Damian Smuga, Joanna Hucz-Kalitowska, Malgorzata Teska-Kaminska, Varvara Vialichka, Krzysztof Dubiel, Bozena Kaminska, Maciej Wieczorek and Jerzy Pieczykolan
Molecular Pharmacology August 4, 2021, MOLPHARM-AR-2021-000260; DOI: https://doi.org/10.1124/molpharm.121.000260
Katarzyna Bazydlo-Guzenda
1Research and Development Centre, Celon Pharma SA, Poland
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  • For correspondence: katarzyna.bazydlo@celonpharma.com
Pawel Buda
1Research and Development Centre, Celon Pharma SA, Poland
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Mikolaj Matloka
1Research and Development Centre, Celon Pharma SA, Poland
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Mateusz Mach
1Research and Development Centre, Celon Pharma SA, Poland
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Filip Stelmach
1Research and Development Centre, Celon Pharma SA, Poland
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Radoslaw Dzida
1Research and Development Centre, Celon Pharma SA, Poland
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Damian Smuga
2Research and Development Centre, Celon Pharma, Poland
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Joanna Hucz-Kalitowska
1Research and Development Centre, Celon Pharma SA, Poland
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Malgorzata Teska-Kaminska
1Research and Development Centre, Celon Pharma SA, Poland
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Varvara Vialichka
3Celon Pharma SA, Poland
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Krzysztof Dubiel
1Research and Development Centre, Celon Pharma SA, Poland
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Bozena Kaminska
4Postgraduate School of Molecular Medicine, Medical University of Warsaw, Poland
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Maciej Wieczorek
1Research and Development Centre, Celon Pharma SA, Poland
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Jerzy Pieczykolan
1Research and Development Centre, Celon Pharma SA, Poland
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Abstract

G protein-coupled receptor 40 (GPR40) is a free fatty acid receptor mainly expressed in pancreatic β-cells activated by medium- and long-chain fatty acids and regulating insulin secretion via an increase in cytosolic free calcium ([Ca2+]i). Activation of GPR40 in pancreatic β-cells may improve glycemic control in type 2 diabetes through enhancement of glucose-stimulated insulin secretion. However, the most clinically advanced GPR40 agonist - TAK-875 (fasiglifam) - was withdrawn from phase III due to its hepatotoxicity resulting from the inhibition of pivotal bile acid transporters. Here, we present a new, potent CPL207280 agonist and compare it with fasiglifam in numerous in vitro and in vivo studies. CPL207280 showed greater potency than fasiglifam in a Ca2+ influx assay with a hGPR40 protein (EC50=80 vs. 270 nM, respectively). At the 10 µM concentration, it showed 3.9 times greater enhancement of GSIS in mouse MIN6 pancreatic β cells. In Wistar Han rats and C57BL6 mice challenged with glucose, CPL207280 stimulated 2.5-times greater insulin secretion without causing hypoglycemia at 10 mg/kg compared with fasiglifam. In three diabetic rat models, CPL207280 improved glucose tolerance and increased insulin area under the curve by 212%, 142%, and 347%, respectively. Evaluation of potential off-target activity (Safety47{trade mark, serif}) and selectivity of CPL207280 (at 10 μM) did not show any significant off-target activity. We conclude that CPL207280 is a potent enhancer of glucose-stimulated insulin secretion in animal disease models with no risk of hypoglycemia at therapeutic doses. Therefore, we propose the CPL207280 compound as a compelling candidate for type 2 diabetes treatment.

Significance Statement GPR40 is a well-known and promising target for diabetes. This study is the first to show the safety and effects of CPL207280, a novel GPR40/FFA1 agonist, on glucose homeostasis both in vitro and in vivo in different diabetic animal models. Therefore, we propose the CPL207280 compound as a novel, glucose-lowering agent, overcoming T2D patients' unmet medical needs.

  • animal models
  • diabetes
  • free fatty acid receptors
  • g protein-coupled receptors (GPCRS)
  • Insulin
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 103 (2)
Molecular Pharmacology
Vol. 103, Issue 2
1 Feb 2023
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CPL207280 - a novel GPR40 agonist in diabetic animal models.

Katarzyna Bazydlo-Guzenda, Pawel Buda, Mikolaj Matloka, Mateusz Mach, Filip Stelmach, Radoslaw Dzida, Damian Smuga, Joanna Hucz-Kalitowska, Malgorzata Teska-Kaminska, Varvara Vialichka, Krzysztof Dubiel, Bozena Kaminska, Maciej Wieczorek and Jerzy Pieczykolan
Molecular Pharmacology August 4, 2021, MOLPHARM-AR-2021-000260; DOI: https://doi.org/10.1124/molpharm.121.000260

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CPL207280 - a novel GPR40 agonist in diabetic animal models.

Katarzyna Bazydlo-Guzenda, Pawel Buda, Mikolaj Matloka, Mateusz Mach, Filip Stelmach, Radoslaw Dzida, Damian Smuga, Joanna Hucz-Kalitowska, Malgorzata Teska-Kaminska, Varvara Vialichka, Krzysztof Dubiel, Bozena Kaminska, Maciej Wieczorek and Jerzy Pieczykolan
Molecular Pharmacology August 4, 2021, MOLPHARM-AR-2021-000260; DOI: https://doi.org/10.1124/molpharm.121.000260
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