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Novel Zn2+ Modulated GPR39 Receptor Agonists Do Not Drive Acute Insulin Secretion in Rodents.

Fjellström O, Larsson N, Yasuda S, Tsuchida T, Oguma T, Marley A, Wennberg-Huldt C, Hovdal D, Fukuda H, Yoneyama Y, Sasaki K, Johansson A, Lundqvist S, Brengdahl J, Isaacs RJ, Brown D, Geschwindner S, Benthem L, Priest C, Turnbull A - PLoS ONE (2015)

Bottom Line: A high throughput screen, followed by a medicinal chemistry program, identified three novel potent Zn2+ modulated GPR39 agonists.The results showed a lack of glucose lowering and insulinotropic effects not only in lean mice, but also in diet-induced obese (DIO) mice and Zucker fatty rats.It is concluded that Zn2+ modulated GPR39 agonists do not acutely stimulate insulin release in rodents.

View Article: PubMed Central - PubMed

Affiliation: Medicinal Chemistry CVMD iMed, AstraZeneca R&D Gothenburg, Mölndal, Sweden.

ABSTRACT
Type 2 diabetes (T2D) occurs when there is insufficient insulin release to control blood glucose, due to insulin resistance and impaired β-cell function. The GPR39 receptor is expressed in metabolic tissues including pancreatic β-cells and has been proposed as a T2D target. Specifically, GPR39 agonists might improve β-cell function leading to more adequate and sustained insulin release and glucose control. The present study aimed to test the hypothesis that GPR39 agonism would improve glucose stimulated insulin secretion in vivo. A high throughput screen, followed by a medicinal chemistry program, identified three novel potent Zn2+ modulated GPR39 agonists. These agonists were evaluated in acute rodent glucose tolerance tests. The results showed a lack of glucose lowering and insulinotropic effects not only in lean mice, but also in diet-induced obese (DIO) mice and Zucker fatty rats. It is concluded that Zn2+ modulated GPR39 agonists do not acutely stimulate insulin release in rodents.

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Related in: MedlinePlus

Plasma concentration–time profile of test compounds in the IPGTT using C57BL/6J mice; AZ7914 (A), AZ4237 (B), AZ1395 (C).Compounds were IP administered to fasted C57BL/6J mice at -30 min as described in the Fig 7 legend. Data represent the value of pooled samples from 7 animals.
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pone.0145849.g009: Plasma concentration–time profile of test compounds in the IPGTT using C57BL/6J mice; AZ7914 (A), AZ4237 (B), AZ1395 (C).Compounds were IP administered to fasted C57BL/6J mice at -30 min as described in the Fig 7 legend. Data represent the value of pooled samples from 7 animals.

Mentions: PK data were generated in order to relate compound unbound exposures in the in vivo studies to unbound in vitro potency parameters. Plasma concentration-time profiles for each of the three compounds in both C57BL/6J and DIO mice are depicted in Fig 9 and Fig 10, respectively. Dose dependent exposures were seen in both models, although not always a linear dependency, and there was a trend of more durable exposures in the DIO mice compared to the lean mice. The average exposure between 0 and 30 minutes in Fig 9 for each compound in lean mice were calculated and compared to in vitro data as shown in Fig 11. AZ7914, AZ4237 and AZ1395 all displayed in vivo exposure versus in vitro potency ratios >10 for each of the screens in the presence of Zn2+, suggesting that none of the DMR, IP1/Gαq or cAMP/Gαs + Zn2+ screens were predictive of improved GSIS in vivo. In the absence of Zn2+, the only in vivo exposure versus in vitro potency ratio exceeding 10 was for the DMR assay with AZ1395. Thus, from these data on AZ1395 and the lack of positive in vivo effects, it seems that DMR in vitro potencies in the absence of added Zn2+ does not translate to desired in vivo effects.


Novel Zn2+ Modulated GPR39 Receptor Agonists Do Not Drive Acute Insulin Secretion in Rodents.

Fjellström O, Larsson N, Yasuda S, Tsuchida T, Oguma T, Marley A, Wennberg-Huldt C, Hovdal D, Fukuda H, Yoneyama Y, Sasaki K, Johansson A, Lundqvist S, Brengdahl J, Isaacs RJ, Brown D, Geschwindner S, Benthem L, Priest C, Turnbull A - PLoS ONE (2015)

Plasma concentration–time profile of test compounds in the IPGTT using C57BL/6J mice; AZ7914 (A), AZ4237 (B), AZ1395 (C).Compounds were IP administered to fasted C57BL/6J mice at -30 min as described in the Fig 7 legend. Data represent the value of pooled samples from 7 animals.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4697807&req=5

pone.0145849.g009: Plasma concentration–time profile of test compounds in the IPGTT using C57BL/6J mice; AZ7914 (A), AZ4237 (B), AZ1395 (C).Compounds were IP administered to fasted C57BL/6J mice at -30 min as described in the Fig 7 legend. Data represent the value of pooled samples from 7 animals.
Mentions: PK data were generated in order to relate compound unbound exposures in the in vivo studies to unbound in vitro potency parameters. Plasma concentration-time profiles for each of the three compounds in both C57BL/6J and DIO mice are depicted in Fig 9 and Fig 10, respectively. Dose dependent exposures were seen in both models, although not always a linear dependency, and there was a trend of more durable exposures in the DIO mice compared to the lean mice. The average exposure between 0 and 30 minutes in Fig 9 for each compound in lean mice were calculated and compared to in vitro data as shown in Fig 11. AZ7914, AZ4237 and AZ1395 all displayed in vivo exposure versus in vitro potency ratios >10 for each of the screens in the presence of Zn2+, suggesting that none of the DMR, IP1/Gαq or cAMP/Gαs + Zn2+ screens were predictive of improved GSIS in vivo. In the absence of Zn2+, the only in vivo exposure versus in vitro potency ratio exceeding 10 was for the DMR assay with AZ1395. Thus, from these data on AZ1395 and the lack of positive in vivo effects, it seems that DMR in vitro potencies in the absence of added Zn2+ does not translate to desired in vivo effects.

Bottom Line: A high throughput screen, followed by a medicinal chemistry program, identified three novel potent Zn2+ modulated GPR39 agonists.The results showed a lack of glucose lowering and insulinotropic effects not only in lean mice, but also in diet-induced obese (DIO) mice and Zucker fatty rats.It is concluded that Zn2+ modulated GPR39 agonists do not acutely stimulate insulin release in rodents.

View Article: PubMed Central - PubMed

Affiliation: Medicinal Chemistry CVMD iMed, AstraZeneca R&D Gothenburg, Mölndal, Sweden.

ABSTRACT
Type 2 diabetes (T2D) occurs when there is insufficient insulin release to control blood glucose, due to insulin resistance and impaired β-cell function. The GPR39 receptor is expressed in metabolic tissues including pancreatic β-cells and has been proposed as a T2D target. Specifically, GPR39 agonists might improve β-cell function leading to more adequate and sustained insulin release and glucose control. The present study aimed to test the hypothesis that GPR39 agonism would improve glucose stimulated insulin secretion in vivo. A high throughput screen, followed by a medicinal chemistry program, identified three novel potent Zn2+ modulated GPR39 agonists. These agonists were evaluated in acute rodent glucose tolerance tests. The results showed a lack of glucose lowering and insulinotropic effects not only in lean mice, but also in diet-induced obese (DIO) mice and Zucker fatty rats. It is concluded that Zn2+ modulated GPR39 agonists do not acutely stimulate insulin release in rodents.

Show MeSH
Related in: MedlinePlus