Identification of a novel conformationally constrained glucagon receptor antagonist

Lee, Esther C.Y.; Tu, Meihua; Stevens, Benjamin D.; Bian, Jianwei; Aspnes, Gary E.; Perreault, Christian; Sammons, M. F.; Wright, Stephen W.; Litchfield, John; Kalgutkar, Amit S.; Sharma, Raman; Didiuk, Mary T.; Ebner, D. C.; Filipski, Kevin J.; Brown, Janice A.; Atkinson, Karen; Pfefferkorn, Jeffrey A.; Guzmán-Pérez, Angel

doi:10.1016/j.bmcl.2013.12.090

Cited by 17 publications

(7 citation statements)

References 22 publications

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“…Re-examination in bile duct-cannulated rats revealed that biliary excretion was a major route for drug elimination, even though 40%–45% of the dosed parent compounds was unchanged. Interestingly, a significant difference in clearance was observed in dogs [25.8 mL • min −1 • kg −1 for (+) 16 and 2.7 mL • min −1 • kg −1 for (−) 16 ], which may be caused by an enantio-specific interaction with the biliary efflux transporter(s) in dogs 68 .…”

Section: Small Molecule Gcgr Modulatorsmentioning

confidence: 99%

“…Using the GCGR antagonist NNC0640, a derivative of compound 11 , we were able to determine the 7-TMD crystal structure of human GCGR, thereby providing essential information for designing safer and more efficacious medications to combat metabolic disorders 12 , 68 , 69 . This breakthrough was made in parallel with the determination by a British team of the structure of CRF 1 R bound to the antagonist CP-376395 13 .…”

Section: Structure-activity Relationship Studiesmentioning

confidence: 99%

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Landmark studies on the glucagon subfamily of GPCRs: from small molecule modulators to a crystal structure

et al. 2015

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The glucagon subfamily of class B G protein-coupled receptors (GPCRs) has been proposed to be a crucial drug target for the tretmaent of type 2 diabetes. The challenges associated with determining the crystal structures of class B GPCRs relate to their large amino termini and the lack of available small molecule ligands to stabilize the receptor proteins. Following our discovery of non-peptidic agonists for glucagon-like peptide-1 receptor (GLP-1R) that have therapeutic effects, we initiated collaborative efforts in structural biology and recently solved the three-dimensional (3D) structure of the human glucagon receptor (GCGR) 7-transmembrane domain, providing in-depth information about the underlying signaling mechanisms. In this review, some key milestones in this endeavor are highlighted, including discoveries of small molecule ligands, their roles in receptor crystallization, conformational changes in transmembrane domains (TMDs) upon activation and structure-activity relationship analyses.

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Section: Small Molecule Gcgr Modulatorsmentioning

confidence: 99%

Section: Structure-activity Relationship Studiesmentioning

confidence: 99%

Landmark studies on the glucagon subfamily of GPCRs: from small molecule modulators to a crystal structure

et al. 2015

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“…Since Novo-Nordisk first discovered β-alanine benzamide as an important pharmacophore of GCGR antagonism (Kodra et al, 2008;Lau et al, 2007;Ling et al 2000;Madsen et al, 2009), other research groups have adopted this moiety or its sulfonic acid congener (e.g., LGD-6972) as an essential structure and performed lead optimization by modifying the hydrophobic region to generate novel antagonists. By analyzing known potent antagonists, we determined that their hydrophobic parts have a rotatable carbon (Lee et al, 2014) and most of the reported compounds contain a stereogenic carbon center at the benzylic position, which could be disadvantageous during the drug discovery process in terms of eutomer purity and cost of synthesis. Considering the structural features of known compounds and novelty of our designed antagonists, we predicted that biphenylsulfonamides would be strong candidates, as shown in Figure 2.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and anti‐diabetic activity of novel biphenylsulfonamides as glucagon receptor antagonists

et al. 2021

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Type 2 diabetes is characterized by chronic hyperglycemia. Insulin, a hormone secreted from pancreatic β-cells, decreases blood glucose levels, and glucagon, a hormone secreted from pancreatic α-cells, increases blood glucose levels by counterregulation of insulin through stimulation of hepatic glucose production. In diabetic patients, dysregulation of glucagon secretion contributes to hyperglycemia. Thus, inhibition of the glucagon receptor is one strategy for the treatment of hyperglycemia in type 2 diabetes. In this paper, we report a series of biphenylsulfonamide derivatives that were designed, synthesized, and then evaluated by cAMP and hepatic glucose production assays as glucagon receptor antagonists. Of these, compound 7aB-3 decreased glucagon-induced cAMP production and glucagon-induced glucose production in the in vitro assays. Glucagon challenge tests and glucose tolerance tests showed that compound 7aB-3 significantly inhibited glucagon-induced glucose increases and improved glucose tolerance. These results suggest that compound 7aB-3 has therapeutic potential for the treatment of type 2 diabetes.

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“…47 A number of cyclic constraints were introduced, with 1,2-transcyclopentane 25 resulting in the highest lipophilic efficiency among these constrained analogs.…”

mentioning

confidence: 99%

Recent progress in the development of small-molecule glucagon receptor antagonists

Sammons

Lee

2015

Bioorganic & Medicinal Chemistry Letters

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Identification of a novel conformationally constrained glucagon receptor antagonist

Cited by 17 publications

References 22 publications

Landmark studies on the glucagon subfamily of GPCRs: from small molecule modulators to a crystal structure

Landmark studies on the glucagon subfamily of GPCRs: from small molecule modulators to a crystal structure

Synthesis and anti‐diabetic activity of novel biphenylsulfonamides as glucagon receptor antagonists

Recent progress in the development of small-molecule glucagon receptor antagonists

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