Chapter 7. Recent Advances in the Discovery of GPR119 Agonists

Shah, Unmesh; Edmondson, Scott D.; Szewczyk, Jason W.

doi:10.1039/9781849735322-00177

Cited by 8 publications

(6 citation statements)

References 34 publications

(68 reference statements)

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“…Способность снижать массу тела в экспериментальных исследованиях отмечена для некоторых агонистов GPR119 (PSN632408, PSN821 и GSK2041706), которые уменьшали массу тела подопытных животных, в том числе и за счет наличия гипофагического эффекта [17]. Комбинированное введение одного из агонистов GPR119 и метформина при терапии ожирения в эксперименте значительно повышало эффективность препаратов [9].…”

Section: Discussionunclassified

Influence of novel GPR119 agonist in combination with metformin and sitagliptin on glycemia, body weight and food intake in rats fed a high-fat diet

et al. 2019

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BACKGROUND: Metabolic syndrome and obesity are often precursors of type 2 diabetes mellitus (DM), and current recommendations indicate the advisability of early initiation of drug therapy at the stage of prediabetes. Drugs with incretin activity are one of the priority groups for monotherapy of type 2 diabetes in the onset of the disease, and certain drugs are used to treat obesity. GPR119 agonists increase the secretion of endogenous incretins, and their effectiveness in the treatment of type 2 diabetes and obesity in mono- and combination therapy is currently being actively studied. AIM. To evaluate of the effect of administration of a GPR119 receptor agonist, its combination with metformin or sitagliptin on body weight, food intake and glycemia in rats under a high-calorie diet. MATERIALS AND METHODS: The study was conducted on 56 outbred female rats aged 78 months and an initial weight of 305320 g. Compound ZB-16 is a highly active GPR119 receptor agonist (EC50 = 7 nM). For 12 weeks, the animals were kept on a high-fat and carbohydrate diet and at the same time received the compound ZB-16, metformin and sitagliptin, or its combination (ZB-16 + metformin and ZB-16 + sitagliptin). During the experiment, the weight of the animals, the mass of feed eaten, as well as the level of glycemia after 6 hours of fasting and with an oral glucose load were assessed. RESULTS: In animals of the control group that were on a high-calorie and fatty diet for 12 weeks, an increase in body weight, glycemia and a decrease in the rate of glucose utilization were observed. The introduction of the GPR119 agonist (ZB-16) for 12 weeks led to a significant reduction in the amount of food consumed, limited weight gain and prevented the development of carbohydrate metabolism disorders. The addition of sitagliptin and especially metformin to therapy with the GPR119 agonist significantly increased the effectiveness of therapy compared to the control group, which was expressed in the normalization of animal body weight and glycemia (p 0.05). CONCLUSIONS: The introduction of a combination of the GPR119 agonist (compound ZB-16) with metformin and sitagliptin is more effective than monotherapy in terms of weight gain, food intake, and also prevents the development of carbohydrate metabolism disorders in animals when kept on a high-fat and carbohydrate diet.

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Section: Discussionunclassified

Influence of novel GPR119 agonist in combination with metformin and sitagliptin on glycemia, body weight and food intake in rats fed a high-fat diet

et al. 2019

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“… Increase in potency and intrinsic activity in comparison to OEA was achieved by replacement of the pyridine ring by the methylsulfonylphenyl moiety and modification of the spacer, as exemplified by compounds 25 (PSN-119-2) and 26 (PSN-119-1M) . Many companies have reported series which correspond to Prosidion-like GPR119 agonists taking advantage of an easily assembled ether unit to vary both spacer type and length and thus the orientation between the terminal groups. − …”

Section: Prosidion-like Gpr119 Agonistsmentioning

confidence: 99%

“…As a result of these efforts PSN821 (structure not disclosed) from Prosidion (now Astellas), 2 from Metabolex (now CymaBay Therapeutics) and 1 from GSK have entered the clinical stage (Table ) and their preclinical data and results from the first clinical trials have been reported in some detail. , PSN821 and 1 have been discontinued after phase II trials, while CymaBay is exploring partnering options for 2 at the phase II stage.…”

Section: Prosidion-like Gpr119 Agonistsmentioning

confidence: 99%

“…The G protein-coupled receptor 119 (GPR119) has emerged as an important target for a new potential oral treatment of T2DM as evident from the numerous patent applications in this field. , The strong interest stems from animal studies with GPR119 agonists showing a glucose-dependent effect on blood glucose levels by concomitant release of insulin from pancreatic beta cells and incretins from intestinal cells. The identification and optimization of such agonists has been described in a number of reviews. − However, several clinical candidates (Table and Chart ) have been discontinued, often without disclosure of the underlying reasons. This perspective will discuss recently published efforts and strategies in overcoming difficulties in the development of GPR119 agonists without claiming to be comprehensive.…”

Section: Introductionmentioning

confidence: 99%

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G Protein-Coupled Receptor 119 (GPR119) Agonists for the Treatment of Diabetes: Recent Progress and Prevailing Challenges

et al. 2015

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In this Perspective, recent advances and challenges in the development of GPR119 agonists as new oral antidiabetic drugs will be discussed. Such agonists are expected to exhibit a low risk to induce hypoglycemia as well as to have a beneficial impact on body weight. Many pharmaceutical companies have been active in the search for GPR119 agonists, making it a highly competitive area in the industrial environment. Several GPR119 agonists have been entered into clinical studies, but many have failed either in phase I or II and none has progressed beyond phase II. Herein we describe the strategies chosen by the different medicinal chemistry teams in academia and the pharmaceutical industry to improve potency, physicochemical properties, pharmacokinetics, and the safety profile of GPR119 agonists in the discovery phase in order to improve the odds for successful development.

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“…Agonism of GPR119 has been shown to increase the secretion of incretins from L-cells (e.g., glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) and to stimulate the release of insulin from pancreatic β-cells . Consequently, agonism of GPR119 has been viewed as having considerable potential in the treatment of diabetes. , …”

Section: Introductionmentioning

confidence: 99%

Circumventing Seizure Activity in a Series of G Protein Coupled Receptor 119 (GPR119) Agonists

et al. 2014

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Agonism of GPR119 is viewed as a potential therapeutic approach for the treatment of type II diabetes and other elements of metabolic syndrome. During progression of a previously disclosed candidate 1 through mice toxicity studies, we observed tonic-clonic convulsions in several mice at high doses. An in vitro hippocampal brain slice assay was used to assess the seizure liability of subsequent compounds, leading to the identification of an aryl sulfone as a replacement for the 3-cyano pyridyl group. Subsequent optimization to improve the overall profile, specifically with regard to hERG activity, led to alkyl sulfone 16. This compound did not cause tonic-clonic convulsions in mice, had a good pharmacokinetic profile, and displayed in vivo efficacy in murine models. Importantly, it was shown to be effective in wild-type (WT) but not GPR119 knockout (KO) animals, consistent with the pharmacology observed being due to agonism of GPR119.

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Chapter 7. Recent Advances in the Discovery of GPR119 Agonists

Cited by 8 publications

References 34 publications

Influence of novel GPR119 agonist in combination with metformin and sitagliptin on glycemia, body weight and food intake in rats fed a high-fat diet

Influence of novel GPR119 agonist in combination with metformin and sitagliptin on glycemia, body weight and food intake in rats fed a high-fat diet

G Protein-Coupled Receptor 119 (GPR119) Agonists for the Treatment of Diabetes: Recent Progress and Prevailing Challenges

Circumventing Seizure Activity in a Series of G Protein Coupled Receptor 119 (GPR119) Agonists

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