Cyclobutane Derivatives As Novel Nonpeptidic Small Molecule Agonists of Glucagon-Like Peptide-1 Receptor

Liu, Qing; Li, Na; Yuan, Yunyun; Lu, Huili; Wu, Xiaoyan; Zhou, Chang; He, Min; Su, Haoran; Zhang, Meng; Wang, Jia; Wang, Bao; Wang, You; Ma, Dawei; Yang, Yong; Weiss, Hans‐Christoph; Gesing, Ernst R. F.; Liao, Jiayu; Wang, Mingwei

doi:10.1021/jm201150j

Cited by 49 publications

(59 citation statements)

References 28 publications

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“…In addition to the endogenous peptide hormones, the small molecule GLP-1R agonists Boc5, S4P, and WB4 -24 also directly bind the receptor ECD (27,28) and require the ECD for signaling (Fig. 10), consistent with a critical role of the ECD in mediating conformational changes in the TMD and intracellular loops.…”

Section: Discussionmentioning

confidence: 72%

“…Interestingly, none of them appears to simply bind the GLP-1R TMD. One set of compounds, exemplified by the large substituted cyclobutanes Boc5 (27), S4P (27), and WB4 -24 (28,29) (Fig. 10A) competed with the ECD binding antagonist exendin(9 -39) (an N-terminally truncated, non-TMD interacting version of the Gila Monster GLP-1R agonist extendin-4; Ref.…”

Section: Small Molecule Glp-1r Modulators Mimic Endogenous Peptide Homentioning

confidence: 99%

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Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors

Zhao

Yin

Yang

et al. 2016

Journal of Biological Chemistry

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G protein-coupled receptors (GPCRs) from the secretin-like (class B) family are key players in hormonal homeostasis and are important drug targets for the treatment of metabolic disorders and neuronal diseases. They consist of a large N-terminal extracellular domain (ECD) and a transmembrane domain (TMD) with the GPCR signature of seven transmembrane helices. Class B GPCRs are activated by peptide hormones with their C termini bound to the receptor ECD and their N termini bound to the TMD. It is thought that the ECD functions as an affinity trap to bind and localize the hormone to the receptor. This in turn would allow the hormone N terminus to insert into the TMD and induce conformational changes of the TMD to activate downstream signaling. In contrast to this prevailing model, we demonstrate that human class B GPCRs vary widely in their requirement of the ECD for activation. In one group, represented by corticotrophin-releasing factor receptor 1 (CRF 1 R), parathyroid hormone receptor (PTH1R), and pituitary adenylate cyclase activating polypeptide type 1 receptor (PAC1R), the ECD requirement for high affinity hormone binding can be bypassed by induced proximity and mass action effects, whereas in the other group, represented by glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), the ECD is required for signaling even when the hormone is covalently linked to the TMD. Furthermore, the activation of GLP-1R by small molecules that interact with the intracellular side of the receptor is dependent on the presence of its ECD, suggesting a direct role of the ECD in GLP-1R activation.The class B or secretin family of GPCRs consists of 15 receptors for peptide hormones that include glucagon, glucagon-like peptides, parathyroid hormone, and calcitonin (Fig. 1A). These receptors are important drug targets for many human diseases including diabetes, neurodegeneration, cardiovascular diseases, and psychiatric disorders. The full-length receptors consist of two modular domains: a globular extracellular domain (ECD) 3 defined by three conserved disulfide bonds and a TMD that contains seven transmembrane helices (1-4). The ECD is responsible for the high affinity and specificity of hormone binding, and the TMD is required for receptor activation and signal coupling to downstream G proteins and other signaling effectors (4). Peptide hormone binding is thought to proceed through fast binding of its C terminus to the ECD followed by a slower association of the peptide N terminus with the receptor TMD (5), which leads to conformational changes in the receptor TMD and the receptor activation. The activated receptors are coupled primarily to stimulatory G proteins, resulting in elevation of the intracellular cAMP level.Structures of the ECDs of class B GPCRs in complex with their peptide ligands have been determined by x-ray crystallography (1, 6 -9) and NMR (10) and have provided useful information about structural mechanisms of ligand recognition and selectivity (2, 11). Only recently, crystal structures of t...

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Section: Discussionmentioning

confidence: 72%

Section: Small Molecule Glp-1r Modulators Mimic Endogenous Peptide Homentioning

confidence: 99%

Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors

Zhao

Yin

Yang

et al. 2016

Journal of Biological Chemistry

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“…This posttranslational modification of third loop of GLP-1R might represent a possible novel mechanism of receptor activity regulation and a potential target in treatment of T2DM. In conjunction with our determination of the crystal structures of Boc5 [19] and WB4-24 (unpublished data), these latest developments will support us to characterize the binding site and ligand-mediated conformational changes induced by GLP-1, Boc5 or WB4-24, and to facilitate molecular modeling strategies to discover more potent and 'druggable' small molecule agonists.…”

Section: Resultsmentioning

confidence: 87%

“…Among several dozen analogues prepared, WB4-24 demonstrated more potent bioactivities than Boc5 both in vitro (GLP-1R binding and cAMP response) and in vivo (food intake inhibition) [19] . With these results, we designed and performed an array of experiments using the mouse DIO model described above to characterize this compound.…”

Section: Improvementmentioning

confidence: 99%

A continued saga of Boc5, the first non-peptidic glucagon-like peptide-1 receptor agonist with in vivo activities

Guan

Gao

et al. 2012

Acta Pharmacol Sin

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Glucagon-like peptide-1 (GLP-1)-based therapy presents a promising option for treating type 2 diabetes. However, there are several limitations relative to the peptidic GLP-1 mimetics currently on the market or under development. This concern has led to a continued interest in the search for non-peptidic agonists for GLP-1 receptor (GLP-1R). Here, we briefly review the discovery, characterization and current status of a novel class of cyclobutane-derivative-based non-peptidic agonists for GLP-1R, including Boc5 and its newly discovered analogue WB4-24. Although the oral bioavailability of such compounds still poses great challenges, the progress made so far encourages us to identify a truly 'druggable' small molecule agonist for GLP-1R.

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“…Synthetic ago-allosteric modulators currently under preclinical investigation include substituted quinoxaline 76,175–177 and cyclobutane derivatives. 178–180 substituted quinoxaline designated as compound 2 acts as a partial agonist at the GLP-1R, but it is particularly revealing that the efficacy of compound 2 as a cAMP-elevating agent is enhanced rather than reduced by GLP-1R antagonist exendin(9–39). This finding is consistent with the concept that allostery results from binding of compound 2 to a site on the GLP-1R that is not recognized by peptide-based agonists and antagonists.…”

Section: Glp-1 Receptor Agonistsmentioning

confidence: 99%

Regulation of Glucose Homeostasis by GLP-1

Nadkarni

Chepurny

Holz

2014

Progress in Molecular Biology and Translational Science

210

141

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Glucagon-like peptide-1(7–36)amide (GLP-1) is a secreted peptide that acts as a key determinant of blood glucose homeostasis by virtue of its abilities to slow gastric emptying, to enhance pancreatic insulin secretion, and to suppress pancreatic glucagon secretion. GLP-1 is secreted from L cells of the gastrointestinal mucosa in response to a meal, and the blood glucose-lowering action of GLP-1 is terminated due to its enzymatic degradation by dipeptidyl-peptidase-IV (DPP-IV). Released GLP-1 activates enteric and autonomic reflexes while also circulating as an incretin hormone to control endocrine pancreas function. The GLP-1 receptor (GLP-1R) is a G protein-coupled receptor that is activated directly or indirectly by blood glucose-lowering agents currently in use for the treatment of type 2 diabetes mellitus (T2DM). These therapeutic agents include GLP-1R agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, and langlenatide) and DPP-IV inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin). Investigational agents for use in the treatment of T2DM include GPR119 and GPR40 receptor agonists that stimulate the release of GLP-1 from L cells. Summarized here is the role of GLP-1 to control blood glucose homeo-stasis, with special emphasis on the advantages and limitations of GLP-1-based therapeutics.

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Cyclobutane Derivatives As Novel Nonpeptidic Small Molecule Agonists of Glucagon-Like Peptide-1 Receptor

Cited by 49 publications

References 28 publications

Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors

Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors

A continued saga of Boc5, the first non-peptidic glucagon-like peptide-1 receptor agonist with in vivo activities

Regulation of Glucose Homeostasis by GLP-1

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