Design and Synthesis of Novel, Selective GPR40 AgoPAMs

Plummer, Christopher W.; Clements, Matthew J.; Chen, Helen; Rajagopalan, Murali; Josien, Hubert; Hagmann, William K.; Miller, Michael D.; Trujillo, María E.; Kirkland, Melissa; Kosinski, Daniel; Mane, Joel; Pachanski, Michele; Cheewatrakoolpong, Boonlert; Nolting, Andrew; Orr, Robert K.; Christensen, Melodie; Campeau, Louis‐Charles; Wright, Michael; Bugianesi, Rossana; Souza, Sarah; Zhang, Xiaoping; Salvo, Jerry Di; Weinglass, Adam B.; Tschirret-Guth, Richard A.; Nargund, Ravi P.; Howard, Andrew D.; Colletti, Steven L.

doi:10.1021/acsmedchemlett.6b00443

Cited by 28 publications

(38 citation statements)

References 21 publications

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“…4A). The effects observed with fasiglifam are similar to those previously reported in the literature (Yabuki et al, 2013;Lu et al, 2017;Plummer et al, 2017) and are consistent with the allosteric nature of this compound.…”

Section: Gpr40 Full Agonists Induce Coupling To Ga12supporting

confidence: 90%

GPR40-Mediated Gα12 Activation by Allosteric Full Agonists Highly Efficacious at Potentiating Glucose-Stimulated Insulin Secretion in Human Islets

et al. 2018

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GPR40 is a clinically validated molecular target for the treatment of diabetes. Many GPR40 agonists have been identified to date, with the partial agonist fasiglifam (TAK-875) reaching phase III clinical trials before its development was terminated due to off-target liver toxicity. Since then, attention has shifted toward the development of full agonists that exhibit superior efficacy in preclinical models. Full agonists bind to a distinct binding site, suggesting conformational plasticity and a potential for biased agonism. Indeed, it has been suggested that alternative pharmacology may be required for meaningful efficacy. In this study, we described the discovery and characterization of Compound A, a newly identified GPR40 allosteric full agonist highly efficacious in human islets at potentiating glucose-stimulated insulin secretion. We compared Compound A-induced GPR40 activity to that induced by both fasiglifam and AM-1638, another allosteric full agonist previously reported to be highly efficacious in preclinical models, at a panel of G proteins. Compound A was a full agonist at both the Gq and Gi2 pathways, and in contrast to fasiglifam Compound A also induced G12 coupling. Compound A and AM-1638 displayed similar activity at all pathways tested. The G/G-mediated signaling pathway has been linked to protein kinase D activation as well as actin remodeling, well known to contribute to the release of insulin vesicles. Our data suggest that the pharmacology of GPR40 is complex and that G12/G13-mediated signaling, which may contribute to GPR40 agonists therapeutic efficacy, is a specific property of GPR40 allosteric full agonists.

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Section: Gpr40 Full Agonists Induce Coupling To Ga12supporting

confidence: 90%

GPR40-Mediated Gα12 Activation by Allosteric Full Agonists Highly Efficacious at Potentiating Glucose-Stimulated Insulin Secretion in Human Islets

et al. 2018

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“…Furthermore, these properties are hypothesized to contribute to greater glucose lowering acutely in vivo with AgoPAMs compared to partial agonists. These acute data of the effects of AgoPAMs in mice were corroborated by, and extended in, diabetic GK rats where AgoPAMs were shown to have enhanced glucose lowering compared to partial agonist; an effect that was durable up to two weeks of treatment [ 5 ]. The long term effects of AgoPAM treatment on insulin and GLP-1 secretion are not known.…”

Section: Introductionmentioning

confidence: 87%

GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent

et al. 2017

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GPR40 agonists are effective antidiabetic agents believed to lower glucose through direct effects on the beta cell to increase glucose stimulated insulin secretion. However, not all GPR40 agonists are the same. Partial agonists lower glucose through direct effects on the pancreas, whereas GPR40 AgoPAMs may incorporate additional therapeutic effects through increases in insulinotrophic incretins secreted by the gut. Here we describe how GPR40 AgoPAMs stimulate both insulin and incretin secretion in vivo over time in diabetic GK rats. We also describe effects of AgoPAMs in vivo to lower glucose and body weight beyond what is seen with partial GPR40 agonists in both the acute and chronic setting. Further comparisons of the glucose lowering profile of AgoPAMs suggest these compounds may possess greater glucose control even in the presence of elevated glucagon secretion, an unexpected feature observed with both acute and chronic treatment with AgoPAMs. Together these studies highlight the complexity of GPR40 pharmacology and the potential additional benefits AgoPAMs may possess above partial agonists for the diabetic patient.

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“…When the binding data obtained for compounds AMG‐837 ( 14 ), AM‐1638 ( 15 ), and AM‐5262 ( 16 ) were compared, it was observed that the last two shared the same interaction site, whereas AMG‐837 shows cooperativity with AM‐1638 and AM‐5262 by highlighting its allosteric binding behavior . This allosteric modulation can lead to superior efficacy when compared to partial agonists as the positive allosteric modulation of the full agonists increase the levels of receptor activation, which can be more than 100% of activation …”

Section: Gpr40 Agonistsmentioning

confidence: 99%

“…This recent project developed compound 19 with EC 50 = 1.1 n m and 428% of activation of GPR40. This compound showed a very promising profile for glycemic control in diabetic patients …”

Section: Gpr40 Agonistsmentioning

confidence: 99%

Structural basis for the agonist action at free fatty acid receptor 1 (FFA1R or GPR40)

et al. 2017

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G-protein-coupled receptor 40 (GPR40) was recently identified as an interesting target for treatment of type 2 diabetes. The high level of expression in pancreatic beta cells and the dependence of glucose on stimulating the secretion of insulin led to great excitement in this field. The identification of this target was followed by the development of a series of agonists with great potential for the treatment of diabetes. All known agonists have the presence of a pharmacophoric carboxylic acid group in their structure, which makes several polar interactions at the binding site of this receptor. In this report, we provide a review of the structure-activity relationships of GPR40 agonists with a focus on the main strategies of medicinal chemistry used to develop each one of the main structural patterns exploited for this purpose. Additionally, we provide a general model for the design of GPR40 ligands that can help researchers to follow up some strategies and implement them in the development of novel agonists of this receptor.

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Design and Synthesis of Novel, Selective GPR40 AgoPAMs

Cited by 28 publications

References 21 publications

GPR40-Mediated Gα12 Activation by Allosteric Full Agonists Highly Efficacious at Potentiating Glucose-Stimulated Insulin Secretion in Human Islets

GPR40-Mediated Gα12 Activation by Allosteric Full Agonists Highly Efficacious at Potentiating Glucose-Stimulated Insulin Secretion in Human Islets

GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent

Structural basis for the agonist action at free fatty acid receptor 1 (FFA1R or GPR40)

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