Nonpeptide Glucagon-like Peptide-1 Receptor Research Articles

Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study

Orforglipron, an oral, non-peptide glucagon-like peptide-1 (GLP-1) receptor agonist, is in development for type 2 diabetes and obesity. We assessed the efficacy and safety of orforglipron versus placebo or dulaglutide in participants with type 2 diabetes. In this 26-week, phase 2, double-blind, randomised, multicentre study, participants were recruited from 45 centres (private clinics, hospitals, and research centers) in the USA, Hungary, Poland, and Slovakia. Adult participants aged 18 years or older with type 2 diabetes treated with diet and exercise, with or without metformin, and with a glycated haemoglobin (HbA1c) of 7·0-10·5%, and stable BMI of 23 kg/m2 or more, were randomly assigned (5:5:5:5:5:3:3:3:3) via an interactive web-response system to placebo, dulaglutide 1·5 mg once per week, or orforglipron 3 mg, 12 mg, 24 mg, 36 mg (group 1), 36 mg (group 2), 45 mg (group 1), or 45 mg (group 2) once per day with no food or water restrictions. Two different dose escalation regimens were evaluated for each of the 36 mg and 45 mg cohorts. Participants were masked to the study drug, dulaglutide, and placebo. The primary efficacy outcome The primary efficacy outcome was mean change in HbA1c from baseline with orforglipron versus placebo at week 26. Efficacy was analysed in all randomly assigned participants who received at least one dose of study drug and excluded data after the permanent discontinuation of study drug or initiation of rescue medication. Safety was analysed in all participants who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT05048719) and is completed. Between Sept 15, 2021, and Sept 30, 2022, 569 participants were screened and 383 were enrolled and randomly assigned to a group. 352 (92%) completed the study and 303 (79%) completed 26 weeks of treatment. At baseline, the mean age was 58·9 years, HbA1c was 8·1%, BMI was 35·2 kg/m2, 226 (59%) were men, and 157 (41%) were women. At week 26, mean change in HbA1c with orforglipron was up to -2·10% (-1·67% placebo adjusted), versus -0·43% with placebo and -1·10% with dulaglutide. HbA1c reduction was statistically superior with orforglipron versus placebo (estimated treatment difference -0·8% to -1·7%). Change in mean bodyweight at week 26 was up to -10·1 kg (95% CI -11·5 to -8·7; 7·9 kg placebo adjusted [-9·9 to -5·9]) with orforglipron versus -2·2 kg (-3·6 to -0·7) for placebo and -3·9 kg (-5·3 to -2·4) for dulaglutide. The incidence of treatment-emergent adverse events ranged from 61·8% to 88·9% in orforglipron-treated participants, compared with 61·8% with placebo and 56·0% with dulaglutide. The majority were gastrointestinal events (44·1% to 70·4% with orforglipron, 18·2% with placebo, and 34·0% with dulaglutide) of mild to moderate severity. Three participants receiving orforglipron and one participant receiving dulaglutide had clinically significant (<54 mg/dL [<3 mmol/L]) hypoglycaemia and no participants had severe hypoglycaemia. One death occurred in the placebo group and was not related to study treatment. In this phase 2 trial the novel, oral, non-peptide GLP-1 receptor agonist orforglipron at doses of 12 mg or greater showed significant reductions in HbA1c and bodyweight compared with placebo or dulaglutide. The adverse event profile was similar to other GLP-1 receptor agonists in similar stage of development. Orforglipron might provide an alternative to injectable GLP-1 receptor agonists and oral semaglutide, with the prospect of less burdensome administration to achieve treatment goals in people with type 2 diabetes. Eli Lilly and Company.

Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity

BackgroundObesity is a major risk factor for many leading causes of illness and death worldwide. Data are needed regarding the efficacy and safety of the nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist orforglipron as a once-daily oral therapy for weight reduction in adults with obesity.MethodsIn this phase 2, randomized, double-blind trial, we enrolled adults with obesity, or with overweight plus at least one weight-related coexisting condition, and without diabetes. Participants were randomly assigned to receive orforglipron at one of four doses (12, 24, 36, or 45 mg) or placebo once daily for 36 weeks. The percentage change from baseline in body weight was assessed at week 26 (primary end point) and at week 36 (secondary end point).ResultsA total of 272 participants underwent randomization. At baseline, the mean body weight was 108.7 kg, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 37.9. At week 26, the mean change from baseline in body weight ranged from −8.6% to −12.6% across the orforglipron dose cohorts and was −2.0% in the placebo group. At week 36, the mean change ranged from −9.4% to −14.7% with orforglipron and was −2.3% with placebo. A weight reduction of at least 10% by week 36 occurred in 46 to 75% of the participants who received orforglipron, as compared with 9% who received placebo. The use of orforglipron led to improvement in all prespecified weight-related and cardiometabolic measures. The most common adverse events reported with orforglipron were gastrointestinal events, which were mild to moderate, occurred primarily during dose escalation, and led to discontinuation of orforglipron in 10 to 17% of participants across dose cohorts. The safety profile of orforglipron was consistent with that of the GLP-1 receptor agonist class.ConclusionsDaily oral orforglipron, a nonpeptide GLP-1 receptor agonist, was associated with weight reduction. Adverse events reported with orforglipron were similar to those with injectable GLP-1 receptor agonists. (Funded by Eli Lilly; GZGI ClinicalTrials.gov number, NCT05051579.)

Design, synthesis, and biological evaluation of a small molecule oral agonist of the glucagon-like-peptide-1 receptor

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.

Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist

Glucagon-like peptide-1 receptor (GLP-1R) agonists are efficacious antidiabetic medications that work by enhancing glucose-dependent insulin secretion and improving energy balance. Currently approved GLP-1R agonists are peptide based, and it has proven difficult to obtain small-molecule activators possessing optimal pharmaceutical properties. We report the discovery and mechanism of action of LY3502970 (OWL833), a nonpeptide GLP-1R agonist. LY3502970 is a partial agonist, biased toward G protein activation over β-arrestin recruitment at the GLP-1R. The molecule is highly potent and selective against other class B G protein-coupled receptors (GPCRs) with a pharmacokinetic profile favorable for oral administration. A high-resolution structure of LY3502970 in complex with active-state GLP-1R revealed a unique binding pocket in the upper helical bundle where the compound is bound by the extracellular domain (ECD), extracellular loop 2, and transmembrane helices 1, 2, 3, and 7. This mechanism creates a distinct receptor conformation that may explain the partial agonism and biased signaling of the compound. Further, interaction between LY3502970 and the primate-specific Trp33 of the ECD informs species selective activity for the molecule. In efficacy studies, oral administration of LY3502970 resulted in glucose lowering in humanized GLP-1R transgenic mice and insulinotropic and hypophagic effects in nonhuman primates, demonstrating an effect size in both models comparable to injectable exenatide. Together, this work determined the molecular basis for the activity of an oral agent being developed for the treatment of type 2 diabetes mellitus, offering insights into the activation of class B GPCRs by nonpeptide ligands.

Glucagon-Like Peptide-1 and Its Class B G Protein-Coupled Receptors: A Long March to Therapeutic Successes.

The glucagon-like peptide (GLP)-1 receptor (GLP-1R) is a class B G protein–coupled receptor (GPCR) that mediates the action of GLP-1, a peptide hormone secreted from three major tissues in humans, enteroendocrine L cells in the distal intestine, α cells in the pancreas, and the central nervous system, which exerts important actions useful in the management of type 2 diabetes mellitus and obesity, including glucose homeostasis and regulation of gastric motility and food intake. Peptidic analogs of GLP-1 have been successfully developed with enhanced bioavailability and pharmacological activity. Physiologic and biochemical studies with truncated, chimeric, and mutated peptides and GLP-1R variants, together with ligand-bound crystal structures of the extracellular domain and the first three-dimensional structures of the 7-helical transmembrane domain of class B GPCRs, have provided the basis for a two-domain–binding mechanism of GLP-1 with its cognate receptor. Although efforts in discovering therapeutically viable nonpeptidic GLP-1R agonists have been hampered, small-molecule modulators offer complementary chemical tools to peptide analogs to investigate ligand-directed biased cellular signaling of GLP-1R. The integrated pharmacological and structural information of different GLP-1 analogs and homologous receptors give new insights into the molecular determinants of GLP-1R ligand selectivity and functional activity, thereby providing novel opportunities in the design and development of more efficacious agents to treat metabolic disorders.

Positive Allosteric Modulation of the Glucagon-like Peptide-1 Receptor by Diverse Electrophiles

Therapeutic intervention to activate the glucagon-like peptide-1 receptor (GLP-1R) enhances glucose-dependent insulin secretion and improves energy balance in patients with type 2 diabetes mellitus. Studies investigating mechanisms whereby peptide ligands activate GLP-1R have utilized mutagenesis, receptor chimeras, photo-affinity labeling, hydrogen-deuterium exchange, and crystallography of the ligand-binding ectodomain to establish receptor homology models. However, this has not enabled the design or discovery of drug-like non-peptide GLP-1R activators. Recently, studies investigating 4-(3-benzyloxyphenyl)-2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine (BETP), a GLP-1R-positive allosteric modulator, determined that Cys-347 in the GLP-1R is required for positive allosteric modulator activity via covalent modification. To advance small molecule activation of the GLP-1R, we characterized the insulinotropic mechanism of BETP. In guanosine 5′-3-O-(thio)triphosphate binding and INS1 832-3 insulinoma cell cAMP assays, BETP enhanced GLP-1(9–36)-NH2-stimulated cAMP signaling. Using isolated pancreatic islets, BETP potentiated insulin secretion in a glucose-dependent manner that requires both the peptide ligand and GLP-1R. In studies of the covalent mechanism, PAGE fluorography showed labeling of GLP-1R in immunoprecipitation experiments from GLP-1R-expressing cells incubated with [3H]BETP. Furthermore, we investigated whether other reported GLP-1R activators and compounds identified from screening campaigns modulate GLP-1R by covalent modification. Similar to BETP, several molecules were found to enhance GLP-1R signaling in a Cys-347-dependent manner. These chemotypes are electrophiles that react with GSH, and LC/MS determined the cysteine adducts formed upon conjugation. Together, our results suggest covalent modification may be used to stabilize the GLP-1R in an active conformation. Moreover, the findings provide pharmacological guidance for the discovery and characterization of small molecule GLP-1R ligands as possible therapeutics.

The non-peptide GLP-1 receptor agonist WB4-24 blocks inflammatory nociception by stimulating β-endorphin release from spinal microglia.

Two peptide agonists of the glucagon-like peptide-1 (GLP-1) receptor, exenatide and GLP-1 itself, exert anti-hypersensitive effects in neuropathic, cancer and diabetic pain. In this study, we have assessed the anti-allodynic and anti-hyperalgesic effects of the non-peptide agonist WB4-24 in inflammatory nociception and the possible involvement of microglial β-endorphin and pro-inflammatory cytokines. We used rat models of inflammatory nociception induced by formalin, carrageenan or complete Freund's adjuvant (CFA), to test mechanical allodynia and thermal hyperalgesia. Expression of β-endorphin and pro-inflammatory cytokines was measured using real-time quantitative PCR and fluorescent immunoassays. WB4-24 displaced the specific binding of exendin (9-39) in microglia. Single intrathecal injection of WB4-24 (0.3, 1, 3, 10, 30 and 100 μg) exerted dose-dependent, specific, anti-hypersensitive effects in acute and chronic inflammatory nociception induced by formalin, carrageenan and CFA, with a maximal inhibition of 60-80%. Spinal WB4-24 was not effective in altering nociceptive pain. Subcutaneous injection of WB4-24 was also antinociceptive in CFA-treated rats. WB4-24 evoked β-endorphin release but did not inhibit expression of pro-inflammatory cytokines in either the spinal cord of CFA-treated rats or cultured microglia stimulated by LPS. WB4-24 anti-allodynia was prevented by a microglial inhibitor, β-endorphin antiserum and a μ-opioid receptor antagonist. Our results suggest that WB4-24 inhibits inflammatory nociception by releasing analgesic β-endorphin rather than inhibiting the expression of proalgesic pro-inflammatory cytokines in spinal microglia, and that the spinal GLP-1 receptor is a potential target molecule for the treatment of pain hypersensitivity including inflammatory nociception.

A novel glucagon‐like peptide 1 peptide identified from Ophisaurus harti

Glucagon-like peptide 1 receptor (GLP1R) is a promising target for the treatment of type 2 diabetes. Because of the short half-life of endogenous GLP1 peptide, other GLP1R agonists are considered to be appealing therapeutic candidates. A high-throughput assay has been established to screen for GLP1R agonists in a 60 000-well natural product compound library fractionated from 670 different herbs/materials widely used in traditional Chinese medicines (TCMs). The screening is based on primary screen of GLP1R⁺ reporter gene assay with the counter screen in GLP1R⁻ cell line. An active fraction, A089-147, was identified from the screening. Fraction A089-147 was isolated from dried Ophisaurus harti, and the fact that its GLP1R agonist activity was sensitive to trypsin treatment indicates its peptidic nature. The active ingredient of A089-147 was later identified as O. harti GLP1 through transcriptome analysis. Chemically synthesized O. harti GLP1 showed GLP1R agonist activity and sensitivity to dipeptidase IV digestion. This study illustrated a comprehensive screening strategy to identify novel GLP1R agonists from TCMs libraries and at the same time underlined the difficulty of identifying a non-peptidic GLP1R agonist. The novel O. harti GLP1 peptide yielded from this study confirmed broader application of TCMs libraries in active peptide identification.

Physiology and Emerging Biochemistry of the Glucagon-Like Peptide-1 Receptor

The glucagon-like peptide-1 (GLP-1) receptor is one of the best validated therapeutic targets for the treatment of type 2 diabetes mellitus (T2DM). Over several years, the accumulation of basic, translational, and clinical research helped define the physiologic roles of GLP-1 and its receptor in regulating glucose homeostasis and energy metabolism. These efforts provided much of the foundation for pharmaceutical development of the GLP-1 receptor peptide agonists, exenatide and liraglutide, as novel medicines for patients suffering from T2DM. Now, much attention is focused on better understanding the molecular mechanisms involved in ligand induced signaling of the GLP-1 receptor. For example, advancements in biophysical and structural biology techniques are being applied in attempts to more precisely determine ligand binding and receptor occupancy characteristics at the atomic level. These efforts should better inform three-dimensional modeling of the GLP-1 receptor that will help inspire more rational approaches to identify and optimize small molecule agonists or allosteric modulators targeting the GLP-1 receptor. This article reviews GLP-1 receptor physiology with an emphasis on GLP-1 induced signaling mechanisms in order to highlight new molecular strategies that help determine desired pharmacologic characteristics for guiding development of future nonpeptide GLP-1 receptor activators.

The development of non-peptide glucagon-like peptide-1 receptor agonist for the treatment of type 2 diabetes

Glucagon-like peptide-1 (GLP-1) is the main member of the incretin family and stimulates insulin secretion by binding with its specific receptor on pancreatic β-cells. In addition, GLP-1 exerts broad beneficial effects on the glucose regulation by suppressing food intake and delaying stomach emptying. Now, long acting GLP-1 analogs including exenatide and liraglutide have been approved for the treatment of diabetes mellitus type 2, however long-term injection can limit their use for these chronic patients. In this report, the authors provide a review on the development of non-peptide GLP-1 receptor agonists and introduce a novel agonist DA-15864.

Non-peptidic glucose-like peptide-1 receptor agonists: aftermath of a serendipitous discovery

Glucagon-like peptide-1 (GLP-1) receptor is an ideal target in the development of incretin-based therapies for diabetes and obesity. Two approaches have been adopted: GLP-1 receptor agonists that mimic the effects of native GLP-1 and dipeptidyl peptidase-4 inhibitors that increase endogenous GLP-1 levels. During the past two decades, search for orally active, non-peptidic GLP-1 receptor agonists has been the focal point of research and development activities in many multinational pharmaceutical companies. Such efforts have not resulted in any success thus far. Serendipitous discovery of substituted cyclobutanes represented by Boc5 as a new class of GLP-1 receptor agonists led us to believe that a small molecule approach to class B G-protein coupled receptor agonism is no longer a fantasy but a reality. However, major obstacles still pose great challenges, and the reasons of which are discussed in this perspectives.