A Small-Molecule Oral Agonist of the Human Glucagon-like Peptide-1 Receptor.
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ABSTRACT:
SUBMITTER: Griffith DA
PROVIDER: S-EPMC9234956 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:An absolute or relative deficiency of pancreatic β-cells mass and functionality is a crucial pathological feature common to type 1 diabetes mellitus and type 2 diabetes mellitus. Glucagon-like-peptide-1 receptor (GLP1R) agonists have been the focus of considerable research attention for their ability to protect β-cell mass and augment insulin secretion with no risk of hypoglycemia. Presently commercially available GLP1R agonists are peptides that limit their use due to cost, stability, and mode of administration. To address this drawback, strategically designed distinct sets of small molecules were docked on GLP1R ectodomain and compared with previously known small molecule GLP1R agonists. One of the small molecule PK2 (6-((1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-6H-indolo[2,3-b]quinoxaline) displays stable binding with GLP1R ectodomain and induces GLP1R internalization and increasing cAMP levels. PK2 also increases insulin secretion in the INS-1 cells. The oral administration of PK2 protects against diabetes induced by multiple low-dose streptozotocin administration by lowering high blood glucose levels. Similar to GLP1R peptidic agonists, treatment of PK2 induces β-cell replication and attenuate β-cell apoptosis in STZ-treated mice. Mechanistically, this protection was associated with decreased thioredoxin-interacting protein expression, a potent inducer of diabetic β-cell apoptosis and dysfunction. Together, this report describes a small molecule, PK2, as an orally active nonpeptidic GLP1R agonist that has efficacy to preserve or restore functional β-cell mass.
| S-EPMC9095748 | biostudies-literature
Project description:PurposeThe glucagon-like peptide-1 receptor (GLP-1R) is an effective therapeutic target for type 2 diabetes mellitus (T2DM) and non-alcoholic steatohepatitis (NASH). Research has focused on small-molecule GLP-1R agonists because of their ease of use in oral formulations and improved patient compliance. However, no small-molecule GLP-1R agonists are currently available in the market. We aimed to screen for a potential oral small-molecule GLP-1R agonist and evaluated its effect on blood glucose and NASH.MethodsThe Connectivity map database was used to screen for candidate small-molecule compounds. Molecular docking was performed using SYBYL software. Rat pancreatic islets were incubated in different concentrations glucose solutions, with cinchonine or Exendin (9-39) added to determine insulin secretion levels. C57BL/6 mice, GLP-1R-/- mice and hGLP-1R mice were used to conduct oral glucose tolerance test. In addition, we fed ob/ob mice with the GAN diet to induce the NASH model. Cinchonine (50 mg/kg or 100 mg/kg) was administered orally twice daily to the mice. Serum liver enzymes were measured using biochemical analysis. Liver tissues were examined using Hematoxylin-eosin staining, Oil Red O staining and Sirius Red staining.ResultsBased on the small intestinal transcriptome of geniposide, a recognized small-molecule GLP-1R agonist, we identified that cinchonine exerted GLP-1R agonist-like effects. Cinchonine had a good binding affinity for GLP-1R. Cinchonine promoted glucose-dependent insulin secretion, which could be attenuated significantly by Exendin (9-39), a specific GLP-1R antagonist. Moreover, cinchonine could reduce blood glucose in C57BL/6 and hGLP-1R mice, an effect that could be inhibited with GLP-1R knockout. In addition, cinchonine reduced body weight gain and food intake in ob/ob-GAN NASH mice dose-dependently. 100 mg/kg cinchonine significantly improved liver function by reducing the ALT, ALP and LDH levels. Importantly, 100 mg/kg cinchonine ameliorated hepatic steatosis and fibrosis in NASH mice.ConclusionCinchonine, a potential oral small-molecule GLP-1R agonist, could reduce blood glucose and ameliorate NASH, providing a strategy for developing small-molecule GLP-1R agonists.
| S-EPMC10184894 | biostudies-literature
Project description:Glucagon-like peptide-1 receptor (GLP-1R) agonist-based therapeutics for type 2 diabetes mellitus have attracted worldwide attention. However, there are challenges in the development of small molecule GLP-1R agonists owing to the complexity of ligand recognition and signal induction mechanisms. Here, we attained S6 using virtual screening and fluorescent imaging plate reader (FLIPR)-based calcium assays. The purpose of this study was to identify and characterize S6, a novel small molecule GLP-1R agonist. Data from cellular thermal shift assay (CETSA) and Bio-Layer Interferometry (BLI) indicated that S6 could bind potently with GLP-1R. Radioimmunoassay data showed that S6 potentiated insulin secretion in a glucose-dependent manner and the insulinotropic effect was mediated by GLP-1R. Calcium imaging techniques suggested that S6 elevated the intracellular calcium concentration [(Ca2+)i] by activating GLP-1R. In patch-clamp experiments, we demonstrated that S6 inhibited voltage-dependent K+ (Kv) channels in a GLP-1R-dependent fashion. Besides, S6 significantly prolonged action potential duration but had no effect on voltage-dependent Ca2+ channels. In summary, these findings indicate that S6 stimulates glucose-dependent insulin secretion mainly by acting on GLP-1R, inhibiting Kv channels, increasing (Ca2+)i. This study will provide direction for the screening and development of novel small-molecule agents targeting GLP-1R in the future.
| S-EPMC8116734 | biostudies-literature
Project description:The peptide hormone glucagon-like peptide (GLP)-1 has important actions resulting in glucose lowering along with weight loss in patients with type 2 diabetes. As a peptide hormone, GLP-1 has to be administered by injection. Only a few small-molecule agonists to peptide hormone receptors have been described and none in the B family of the G protein coupled receptors to which the GLP-1 receptor belongs. We have discovered a series of small molecules known as ago-allosteric modulators selective for the human GLP-1 receptor. These compounds act as both allosteric activators of the receptor and independent agonists. Potency of GLP-1 was not changed by the allosteric agonists, but affinity of GLP-1 for the receptor was increased. The most potent compound identified stimulates glucose-dependent insulin release from normal mouse islets but, importantly, not from GLP-1 receptor knockout mice. Also, the compound stimulates insulin release from perfused rat pancreas in a manner additive with GLP-1 itself. These compounds may lead to the identification or design of orally active GLP-1 agonists.
| S-EPMC1783418 | biostudies-literature
Project description:The glucagon-like peptide-1 receptor (GLP-1R) is a family B G protein-coupled receptor and an important drug target for the treatment of type II diabetes, with activation of pancreatic GLP-1Rs eliciting glucose-dependent insulin secretion. Currently, approved therapeutics acting at this receptor are peptide based, and there is substantial interest in small molecule modulators for the GLP-1R. Using a variety of resonance energy transfer techniques, we demonstrate that the GLP-1R forms homodimers and that transmembrane helix 4 (TM4) provides the primary dimerization interface. We show that disruption of dimerization using a TM4 peptide, a minigene construct encoding TM4, or by mutation of TM4, eliminates G protein-dependent high-affinity binding to GLP-1(7-36)NH(2) but has selective effects on receptor signaling. There was <10-fold decrease in potency in cAMP accumulation or ERK1/2 phosphorylation assays but marked loss of intracellular calcium mobilization by peptide agonists. In contrast, there was near-complete abrogation of the cAMP response to an allosteric agonist, compound 2, but preservation of ERK phosphorylation. Collectively, this indicates that GLP-1R dimerization is important for control of signal bias. Furthermore, we reveal that two small molecule ligands are unaltered in their ability to allosterically modulate signaling from peptide ligands, demonstrating that these modulators act in cis within a single receptor protomer, and this has important implications for small molecule drug design.
| S-EPMC3494884 | biostudies-other
Project description:ImportanceCurrently available glucagon-like peptide 1 receptor (GLP-1R) agonists for treating type 2 diabetes (T2D) are peptide agonists that require subcutaneous administration or strict fasting requirements before and after oral administration.ObjectiveTo investigate the efficacy, safety, and tolerability of multiple dose levels of the novel, oral, small molecule GLP-1R agonist danuglipron over 16 weeks.Design, setting, and participantsA phase 2b, double-blind, placebo-controlled, parallel-group, 6-group randomized clinical trial with 16-week double-blind treatment period and 4-week follow-up was conducted from July 7, 2020, to July 7, 2021. Adults with T2D inadequately controlled by diet and exercise, with or without metformin treatment, were enrolled from 97 clinical research sites in 8 countries or regions.InterventionsParticipants received placebo or danuglipron, 2.5, 10, 40, 80, or 120 mg, all orally administered twice daily with food for 16 weeks. Weekly dose escalation steps were incorporated to achieve danuglipron doses of 40 mg or more twice daily.Main outcomes and measuresChange from baseline in glycated hemoglobin (HbA1c, primary end point), fasting plasma glucose (FPG), and body weight were assessed at week 16. Safety was monitored throughout the study period, including a 4-week follow-up period.ResultsOf 411 participants randomized and treated (mean [SD] age, 58.6 [9.3] years; 209 [51%] male), 316 (77%) completed treatment. For all danuglipron doses, HbA1c and FPG were statistically significantly reduced at week 16 vs placebo, with HbA1c reductions up to a least squares mean difference vs placebo of -1.16% (90% CI, -1.47% to -0.86%) for the 120-mg twice daily group and FPG reductions up to a least squares mean difference vs placebo of -33.24 mg/dL (90% CI, -45.63 to -20.84 mg/dL). Body weight was statistically significantly reduced at week 16 compared with placebo in the 80-mg twice daily and 120-mg twice daily groups only, with a least squares mean difference vs placebo of -2.04 kg (90% CI, -3.01 to -1.07 kg) for the 80-mg twice daily group and -4.17 kg (90% CI, -5.15 to -3.18 kg) for the 120-mg twice daily group. The most commonly reported adverse events were nausea, diarrhea, and vomiting.Conclusions and relevanceIn adults with T2D, danuglipron reduced HbA1c, FPG, and body weight at week 16 compared with placebo, with a tolerability profile consistent with the mechanism of action.Trial registrationClinicalTrials.gov Identifier: NCT03985293.
| S-EPMC10203889 | biostudies-literature
Project description:Peptidic agonists of the glucagon-like peptide-1 receptor (GLP-1R) have gained a prominent role in the therapy of type-2 diabetes and are being considered for reducing food intake in obesity. Potential advantages of small molecules acting as positive allosteric modulators (PAMs) of GLP-1R, including oral administration and reduced unwanted effects, could improve the utility of this class of drugs. Here, we describe the discovery of compound 9 (4-{[1-({3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)piperidin-3-yl]methyl}morpholine, V-0219) that exhibits enhanced efficacy of GLP-1R stimulation, subnanomolar potency in the potentiation of insulin secretion, and no significant off-target activities. The identified GLP-1R PAM shows a remarkable in vivo activity, reducing food intake and improving glucose handling in normal and diabetic rodents. Enantioselective synthesis revealed oral efficacy for (S)-9 in animal models. Compound 9 behavior bolsters the interest of a small-molecule PAM of GLP-1R as a promising therapeutic approach for the increasingly prevalent obesity-associated diabetes.
| S-EPMC9014410 | biostudies-literature
Project description:BACKGROUND:Dulaglutide is a new, long-acting glucagon-like peptide analogue in the treatment of type 2 diabetes. It is available in two doses, 0.75 and 1.5 mg, given by injection once weekly. This systematic review reports the effectiveness and safety of dulaglutide in type 2 diabetes in dual and triple therapy. METHODS:MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, and conference abstracts were searched from 2005 to August 2014, and updated in January 2015. Company websites and references of included studies were checked for potentially relevant studies. European Medicines Agency and US Food and Drug Administration websites were searched. RESULTS:Four trials were included. All were manufacturer-funded randomized controlled trials from the Assessment of Weekly Administration of Dulaglutide in Diabetes (AWARD) program. AWARD-1 compared dulaglutide 1.5 mg against exenatide 10 µg twice daily and placebo, AWARD-2 compared dulaglutide 0.75 and 1.5 mg against insulin glargine, AWARD-5 compared dulaglutide 0.75 and 1.5 mg against sitagliptin 100 mg and placebo, and AWARD-6 compared dulaglutide 1.5 mg against liraglutide 1.8 mg. The duration of follow-up in the trials ranged from 26 to 104 weeks. The primary outcome of all the included trials was change in HbA1c. At 26 weeks, greater HbA1c reductions were seen with dulaglutide than with twice daily exenatide (dulaglutide 1.5/0.75 mg: -1.5%/-1.3%; exe: 0.99%) and sitagliptin (1.5/0.75 mg -1.22%/-1.01%; sitagliptin: -0.6%). HbA1c change was greater with dulaglutide 1.5 mg (-1.08%) than with glargine (-0.63%), but not with dulaglutide 0.75 mg (-0.76%). Dulaglutide 1.5 mg was found to be noninferior to liraglutide 1.8 mg. More patients treated with dulaglutide achieved HbA1c targets of <7% and ≤6.5%. Reduction in weight was greater with dulaglutide than with sitagliptin and exenatide. Hypoglycemia was infrequent. The main adverse events were nausea, diarrhea, and vomiting. CONCLUSION:Dulaglutide is effective in the treatment of patients with type 2 diabetes but we need long follow-up data for safety concerns.
| S-EPMC4541559 | biostudies-literature
Project description:We are developing an orally available small-molecule, allosteric TSH receptor (TSHR) agonist for follow-up diagnostics of patients with thyroid cancer. The agonist C2 (NCGC00161870) that we have studied so far is a racemic mixture containing equal amounts of two enantiomers, E1 and E2. As enantiomers of many drugs exhibit different pharmacologic properties, we assessed the properties of E1 and E2. We separated the two enantiomers by chiral chromatography and determined E2 as the (S)-(+) isomer via crystal structure analysis. E1 and E2 were shown to bind differently to a homology model of the transmembrane domain of TSHR in which E2 was calculated to exhibit lower binding energy than E1 and was, therefore, predicted to be more potent than E1. In HEK293 cells expressing human TSHRs, C2, E1, and E2 were equally efficacious in stimulating cAMP production, but their potencies were different. E2 was more potent (EC50 = 18 nM) than C2 (EC50 = 46 nM), which was more potent than E1 (EC50 = 217 nM). In primary cultures of human thyrocytes, C2, E1, and E2 stimulated increases in thyroperoxidase mRNA of 92-, 55-, and 137-fold and in sodium-iodide symporter mRNA of 20-, 4-, and 121-fold above basal levels, respectively. In mice, C2 stimulated an increase in radioactive iodine uptake of 1.5-fold and E2 of 2.8-fold above basal level, whereas E1 did not have an effect. C2 stimulated an increase in serum T4 of 2.4-fold, E1 of 1.9-fold, and E2 of 5.6-fold above basal levels, and a 5-day oral dosing regimen of E2 increased serum T4 levels comparable to recombinant human TSH (rhTSH, Thyrogen(®)). Thus, E2 is more effective than either C2 or E1 in stimulating thyroid function and as efficacious as rhTSH in vivo. E2 represents the next step toward developing an oral drug for patients with thyroid cancer.
| S-EPMC4961696 | biostudies-literature
Project description:Aims/introductionGlucagon-like peptide-1 receptor agonists (GLP-1RA) are used for treatment of type 2 diabetes mellitus worldwide. However, some patients do not respond well to the therapy, and caution must be taken for certain patients, including those with reduced insulin secretory capacity. Thus, it is clinically important to predict the efficacy of GLP-1RA therapy. GLP-1R-targeted imaging has recently emerged to visualize and quantify β-cells. We investigated whether GLP-1R-targeted imaging can predict the efficacy of GLP-1RA treatment.Materials and methodsWe developed 111 Indium-labeled exendin-4 derivative (111 In-Ex4) as a GLP-1R-targeting probe. Diabetic mice were selected from NONcNZO10/LtJ male mice that were fed for different durations with 11% fat chow. After 3-week administration of dulaglutide as GLP-1RA therapy, mice with non-fasting blood glucose levels <300 mg/dL and >300 mg/dL were defined as responders and non-responders, respectively. In addition, ex vivo 111 In-Ex4 pancreatic accumulations (111 In-Ex4 pancreatic values) were examined.ResultsThe non-fasting blood glucose levels after treatment were 172.5 ± 42.4 mg/dL in responders (n = 4) and 330.8 ± 20.7 mg/dL in non-responders (n = 5), respectively. Ex vivo 111 In-Ex4 pancreatic values showed significant correlations with post-treatment glycohemoglobin and glucose area under curve during an oral glucose tolerance test (R2 = 0.76 and 0.80; P < 0.01 and <0.01, respectively). The receiver operating characteristic area under curve for identifying responders by ex vivo 111 In-Ex4 pancreatic values was 1.00 (P < 0.01).ConclusionEx vivo 111 In-Ex4 pancreatic values reflected dulaglutide efficacy, suggesting clinical possibilities for expanding GLP-1R-targeted imaging applications.
| S-EPMC7610126 | biostudies-literature