Discovery and development of CPL207280 as new GPR40/FFA1 agonist

Mach, Mateusz; Bazydlo-Guzenda, Katarzyna; Buda, Pawel; Matłoka, Mikołaj; Dzida, Radoslaw; Stelmach, Filip; Gałązka, Kinga; Wasinska-Kalwa, Malgorzata; Smuga, Damian; Hołowińska, Dagmara; Dawid, Urszula; Gurba-Bryśkiewicz, Lidia; Wisniewski, K.; Dubiel, Krzysztof; Pieczykolan, Jerzy; Wieczorek, Maciej

doi:10.1016/j.ejmech.2021.113810

Cited by 8 publications

(7 citation statements)

References 57 publications

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“…Its reduced molecular weight and lipophilicity minimized the risk of potential side effects, including drug-induced liver injury (DILI). 12 Preclinical studies showed that CPL207280 improved glucose tolerance via glucose-dependent insulin secretion in diabetic animal models without risk of hepatotoxicity. 11,13 The formulation development resulted in a sustained-release (SR) dosage form.…”

Section: Introductionmentioning

confidence: 99%

“…Its modified structure, developed as a metformin (N, N′‐dimethylbiguanide) salt, maintains potency and bioavailability with respect to fasiglifam. Its reduced molecular weight and lipophilicity minimized the risk of potential side effects, including drug‐induced liver injury (DILI) 12 . Preclinical studies showed that CPL207280 improved glucose tolerance via glucose‐dependent insulin secretion in diabetic animal models without risk of hepatotoxicity 11,13 .…”

Section: Introductionmentioning

confidence: 99%

“…We observed a favourable safety profile of CPL207280, with no evidence suggesting potential liver injury.Although one of the most frequently reported AEs in parallel with a headache was elevated ALT and AST levels (five and three cases, respectively), none of these were classified as related or possibly related to the studied drug candidate. The favourable safety profile of CPL207280, designed and described by Mach et al (2021)12 as a Safety assessment during multiple ascending dose study (N = 32). Area under the curve (AUC) 0-6h for glucose values are given as mean and standard deviation (SD) for each cohort on Day 14 (A).…”

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confidence: 99%

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First‐in‐human study of CPL207280, a novel G‐protein‐coupled receptor 40/free fatty acid receptor 1 agonist, in healthy volunteers after single and multiple administration

Bazydło‐Guzenda,

Jarus‐Dziedzic,

Gierczak‐Pachulska

et al. 2024

Diabetes Obesity Metabolism

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AimTo assess the safety, tolerability and pharmacokinetic (PK) profile of single and multiple doses of CPL207280, a new G‐protein‐coupled receptor 40 agonist developed to treat type 2 diabetes (T2D).MethodsThe phase 1 study in healthy volunteers (White, age 18–55 years, body mass index 18.5–29.9 kg/m2) was performed after single (24 subjects, 5–480 mg) and multiple (32 subjects, 60–480 mg) once‐daily administration of CPL207280. The effect of food intake and interaction with metformin were evaluated in additional cohort (12 subjects, 120 mg). The primary objective was the safety and tolerability of CPL207280. Secondary objectives included PK and pharmacodynamic (PD) characteristics (glucose, insulin, C‐peptide, proinsulin, glucagon levels) observed during the 14‐day treatment period.ResultsNo deaths or serious adverse events (AEs) were reported. All reported AEs were classified as unrelated to the study product. No clinically significant differences in safety parameters were observed between cohorts and no food or metformin effect on safety parameters was identified. The ascending dose of CPL207280 caused an increase in the PK parameters maximum observed plasma concentration (Cmax) or area under the plasma concentration–time curve up to 24 h. However, dose‐normalized Cmax decreased with ascending dose. There was no relationship between the CPL207280 dose or prandial state and terminal elimination half‐life and terminal elimination rate constant. No clear relationship between CPL207280 dose and PD area under the effect curve values was observed.ConclusionsCPL207280 was found to be safe and well tolerated by healthy volunteers (with a low risk of hepatotoxicity) for up to 14 days of administration. The PK profile of CPL207280 supports single‐daily administration and justifies further development of this therapy for patients with T2D.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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First‐in‐human study of CPL207280, a novel G‐protein‐coupled receptor 40/free fatty acid receptor 1 agonist, in healthy volunteers after single and multiple administration

Bazydło‐Guzenda,

Jarus‐Dziedzic,

Gierczak‐Pachulska

et al. 2024

Diabetes Obesity Metabolism

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“…However phase III clinical trials with TAK-875 were terminated because of indications of liver toxicity in patients [ 36 ]. As a result, although treatments based on FFA1 agonism may still provide a promising option in the search for new anti-diabetic medications, and a number of additional ligands have already been assessed in rodent models, there has nevertheless been limited progression towards human studies beyond initial phase I safety studies (e.g., [ 37 ]). Importantly, recent research has revealed the remarkable complexity of FFA1 ligand actions providing optimism that with a better knowledge of the underlying processes the next phase will be more effective [ 29 , 38 ].…”

Section: Introduction: Free Fatty Acids (Ffas)mentioning

confidence: 99%

“…These compounds enhance incretin production from enteroendocrine cells and directly stimulate insulin production whilst AP1 and AP3, both of which are reported as full agonists of FFA1, promote insulin and incretin production in diabetic ‘Goto-Kakizaki’ rats, resulting in a reduction in both body mass and blood sugar levels [ 43 , 44 ]. Recently, Mach et al have reported CPL207280 which, in their in vitro studies, was more effective than TAK-875 [ 37 ]. These examples highlight the varying signalling characteristics of different FFA1 activators and the pathways with which the receptor can engage.…”

Section: Introduction: Free Fatty Acids (Ffas)mentioning

confidence: 99%

How Arrestins and GRKs Regulate the Function of Long Chain Fatty Acid Receptors

Alharbi

Tobin

Milligan

2022

IJMS

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FFA1 and FFA4, two G protein-coupled receptors that are activated by long chain fatty acids, play crucial roles in mediating many biological functions in the body. As a result, these fatty acid receptors have gained considerable attention due to their potential to be targeted for the treatment of type-2 diabetes. However, the relative contribution of canonical G protein-mediated signalling versus the effects of agonist-induced phosphorylation and interactions with β-arrestins have yet to be fully defined. Recently, several reports have highlighted the ability of β-arrestins and GRKs to interact with and modulate different functions of both FFA1 and FFA4, suggesting that it is indeed important to consider these interactions when studying the roles of FFA1 and FFA4 in both normal physiology and in different disease settings. Here, we discuss what is currently known and show the importance of understanding fully how β-arrestins and GRKs regulate the function of long chain fatty acid receptors.

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