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Danuglipron
Danuglipron
Danuglipron
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Danuglipron
Clinical data
Other namesPF-06882961
Legal status
Legal status
  • Investigational
Identifiers
  • 2-[[4-[6-[(4-Cyano-2-fluorophenyl)methoxy]pyridin-2-yl]piperidin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC31H30FN5O4
Molar mass555.610 g·mol−1
3D model (JSmol)
  • N#Cc1ccc(COc2cccc(C3CCN(Cc4nc5ccc(C(=O)O)cc5n4C[C@@H]4CCO4)CC3)n2)c(F)c1
  • InChI=1S/C31H30FN5O4/c32-25-14-20(16-33)4-5-23(25)19-41-30-3-1-2-26(35-30)21-8-11-36(12-9-21)18-29-34-27-7-6-22(31(38)39)15-28(27)37(29)17-24-10-13-40-24/h1-7,14-15,21,24H,8-13,17-19H2,(H,38,39)/t24-/m0/s1
  • Key:HYBAKUMPISVZQP-DEOSSOPVSA-N

Danuglipron is a small-molecule GLP-1 agonist, formerly under development by Pfizer[1] that, in an oral formulation, was under investigation as a therapy for diabetes mellitus. Initial results from a randomized controlled trial indicated that it reduced weight and improved diabetic control. The most commonly reported adverse events were nausea, diarrhea, and vomiting.[2][3] However, in April 2025, Pfizer announced it would abandon further development of Danuglipron due to unpredictable liver toxicity.[4]

See also

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References

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Danuglipron

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from Grokipedia
Danuglipron (PF-06882961) is an investigational, oral small-molecule agonist of the (GLP-1R) developed by as a potential treatment for mellitus (T2DM) and . Designed to mimic the GLP-1, it promotes glucose-dependent insulin secretion from pancreatic beta cells, suppresses release, slows gastric emptying, and reduces food intake, thereby improving glycemic control and facilitating without the need for injections common to other GLP-1R agonists. Its is 2-((4-(6-((4-cyano-2-fluorophenyl)methoxy)-2-pyridinyl)-1-piperidinyl)methyl)-1-((2S)-2-oxetanylmethyl)-1H-benzimidazole-6-carboxylic acid, with a molecular formula of C31H30FN5O4. Initial preclinical and early clinical studies demonstrated danuglipron's potency as a non-peptide , with dose-proportional and supporting its . In phase 1 trials involving healthy volunteers and Japanese adults with T2DM, doses up to 120 mg twice daily showed reductions in plasma glucose (up to 40.87 mg/dL), HbA1c (up to 1.41%), and body weight (up to 1.87 kg) over 8 weeks, alongside common gastrointestinal adverse events like and that were mostly mild to moderate. Phase 2 studies further confirmed in T2DM patients, with a 16-week reporting placebo-adjusted HbA1c reductions of 0.49–1.18% and of 2.0–4.2 kg at higher doses, positioning it as a competitive alternative to injectable GLP-1 therapies. Pfizer advanced danuglipron's formulation from twice-daily to a once-daily modified-release version in 2024, selecting a preferred dose after optimization studies involving over 1,400 participants that affirmed its potential for phase 3 trials in chronic . However, development was discontinued in April 2025 following a single case of potential drug-induced in a dose-optimization study (NCT06567327), despite overall liver enzyme elevations aligning with those of approved GLP-1R agonists and no other serious signals in the safety database. plans to share full clinical data through scientific publications or forums, while continuing its broader pipeline in metabolic diseases.

Pharmacology

Mechanism of action

Danuglipron is a small-molecule, non-peptide of the (GLP-1R), a class B G protein-coupled receptor that plays a key role in and . As an orally bioavailable compound, it was optimized through to enhance potency and pharmacokinetic properties suitable for , distinguishing it from traditional peptide-based therapies. Danuglipron functions as a biased , preferentially activating the Gαs-coupled pathway that elevates cyclic AMP (cAMP) levels over β-arrestin recruitment, which may contribute to improved efficacy in glycemic control and appetite suppression with potentially reduced receptor desensitization. At the molecular level, danuglipron binds within the of the GLP-1R, forming key interactions that stabilize the active receptor conformation. Cryo-electron microscopy structures reveal that its moiety engages in an ion-pair interaction with 380 (Arg380^{6.59}), while the binding pocket is capped by the primate-specific 33 (Trp33) residue, which is absent in and explains species-selective activity. These interactions, refined through iterative optimization of the molecule's and moieties, enable receptor activation with an for cAMP production of approximately 13 nM in cells. Upon GLP-1R activation, danuglipron stimulates downstream signaling that promotes insulin secretion from pancreatic β-cells in a glucose-dependent manner, suppresses release from α-cells, delays gastric emptying, and enhances satiety through pathways involving hypothalamic GLP-1R expression. These effects collectively contribute to improved glycemic control and reduced food intake, as observed in preclinical models, with clinical studies noting reductions in HbA1c and body weight. In comparison to peptide-based GLP-1R agonists like , danuglipron's non-peptidic structure allows for oral dosing without the need for injections or modifications for stability against peptidases, though it exhibits lower overall potency (e.g., EC50 of 13 nM versus approximately 6 pM for ) and reduced β-arrestin recruitment, potentially altering the balance of signaling outcomes. This biased profile and small-molecule design represent an advancement in targeting the GLP-1R for metabolic disorders.

Pharmacokinetics

Danuglipron was developed in immediate-release and modified-release oral formulations. The twice-daily immediate-release formulation is typically administered with food to enhance tolerability, while the once-daily modified-release version was designed to further improve gastrointestinal tolerability and support single dosing by achieving sustained plasma levels. Following oral administration, danuglipron is rapidly absorbed, with median time to peak plasma concentrations (T_max) ranging from 2 to 6 hours across doses. It undergoes hepatic uptake primarily via organic anion-transporting polypeptide (OATP) transporters, including OATP1B1, OATP1B3, and OATP2B1, which facilitate its delivery to the liver for clearance. Danuglipron exhibits primarily hepatic clearance, with metabolism occurring mainly through enzymes /5, supplemented by other CYP isoforms, non-CYP enzymes, and conjugation pathways. In healthy individuals, renal is negligible, with less than 0.1% of the unchanged recovered in urine. The apparent oral clearance remains consistent across renal function levels, underscoring its low dependence on renal elimination. The terminal elimination of danuglipron is approximately 5 to 6 hours at , supporting twice-daily dosing for the immediate-release formulation to maintain therapeutic exposure. Food intake has minimal impact on absorption, resulting in comparable area under the curve (AUC) and peak concentration (C_max) values in fed versus fasted states. In individuals with renal impairment, danuglipron exposure increases modestly, with AUC up to 1.4-fold and C_max up to 1.5-fold higher than in those with normal renal function, but these changes are not considered clinically significant. No dose adjustments are necessary for renal impairment; however, caution is recommended due to the drug's reliance on hepatic metabolism and clearance.

Investigational uses

Type 2 diabetes

Danuglipron was under investigation as an oral therapy for mellitus (T2D), particularly for adults whose condition remained inadequately controlled by diet and exercise alone or in combination with metformin. In clinical studies, it targeted patients with baseline HbA1c levels between 7% and 10.5%, demonstrating potential as a non-insulin option to enhance glycemic management in this population. As a small-molecule (GLP-1) receptor agonist, danuglipron acted through glucose-dependent mechanisms to stimulate insulin secretion and suppress release, thereby addressing without substantially increasing the risk of . Key efficacy data from phase 2 trials indicated dose-dependent improvements in glycemic control among T2D patients. At doses ranging from 2.5 mg to 120 mg twice daily, danuglipron produced -adjusted reductions in HbA1c of 0.47% to 1.16% at 16 weeks, with the highest reductions observed at the 120 mg dose. Similarly, fasting plasma glucose levels decreased in a dose-responsive manner, with -adjusted reductions up to 33.24 mg/dL at the same time point and dose. These effects were evident as early as week 2 and sustained through the study duration, supporting danuglipron's role in achieving HbA1c targets below 7% in a greater proportion of participants compared to . As an oral formulation, danuglipron offered a convenient alternative to injectable GLP-1 receptor agonists, potentially improving long-term adherence and compliance in T2D . This attribute was particularly relevant for chronic therapy, where ease of administration could enhance sustained glycemic control. Its glucose-dependent action further positioned it as a safer option for minimizing risk, aligning with prerequisites for effective T2D .

Obesity

Danuglipron was under investigation as an oral glucagon-like peptide-1 receptor agonist (GLP-1RA) for chronic in adults with , defined as a (BMI) of ≥30 kg/m², or ≥27 kg/m² in the presence of weight-related comorbidities such as or , in conjunction with a reduced-calorie diet and increased . This approach targeted sustained weight reduction by addressing the underlying of through GLP-1 receptor activation. In phase 2b trials focused on , danuglipron demonstrated significant placebo-adjusted weight reductions, ranging from 8% to 13% at 32 weeks and 5% to 9.5% at 26 weeks across various doses (80–200 mg twice daily), with higher doses yielding greater effects. These outcomes reflected dose-dependent , where a majority of participants achieved clinically meaningful of ≥5% from baseline, supporting its potential role in . The weight loss induced by danuglipron was mediated primarily through central GLP-1 receptor effects that suppressed appetite and reduced caloric intake, alongside peripheral actions such as delayed gastric emptying. By modulating brain regions involved in hunger regulation, including the , danuglipron promoted signals similar to endogenous GLP-1, contributing to decreased food consumption and overall energy balance. Compared to approved injectable GLP-1 therapies like , danuglipron's oral formulation offered improved patient accessibility and convenience, potentially broadening treatment adherence in management while exhibiting a comparable efficacy and safety profile for gastrointestinal adverse events. In patients with comorbid , these weight loss benefits complemented glycemic improvements observed with danuglipron. Development of danuglipron was discontinued by in April 2025 following a case of potential drug-induced in a dose-optimization study.

Clinical trials

Phase 1 studies

Phase 1 studies of danuglipron (PF-06882961), an oral small-molecule agonist, primarily evaluated its safety, tolerability, (PK), and (PD) in early human trials conducted around 2018–2021. The first-in-human study was a single ascending-dose (SAD) in healthy adult volunteers, designed as a randomized, double-blind, placebo-controlled investigation to assess initial safety and PK following single oral doses. This established preliminary tolerability, with no serious adverse events reported, and demonstrated dose-proportional increases in plasma exposure, supporting progression to multiple-dose evaluations. A key multiple ascending-dose (MAD) study involved 98 adults with (T2D) on stable metformin therapy, randomized across eight cohorts to receive danuglipron (10–200 mg twice daily [BID] or 120–200 mg once daily [QD]) or for 28 days in a double-blind, -controlled . PK analyses showed approximately dose-proportional exposures with BID and QD regimens, characterized by a time to maximum concentration (Tmax) of 3–6 hours and an elimination of about 11 hours, consistent with BID dosing suitability. PD effects included dose-dependent reductions in mean daily glucose (up to 34 mg/dL) and fasting plasma glucose (up to 28 mg/dL), alongside variable postprandial insulin responses, indicating favorable glucose-lowering activity without . Safety was generally favorable, with most adverse events (AEs) mild gastrointestinal issues like and (occurring in 40–60% of participants at higher doses), no serious AEs, and minor increases in (up to 8 bpm) that resolved post-treatment. Additional Phase 1 studies explored specific populations and conditions. In Japanese adults with T2D (n=37), a randomized, double-blind, placebo-controlled MAD trial with BID titration to 40–120 mg over 8 weeks confirmed dose-proportional steady-state PK (AUC24 increasing from 2424 to 6953 ng·h/mL) and PD benefits, including reductions in fasting glucose (40.9 mg/dL) and HbA1c (1.41%). Gastrointestinal AEs were mild to moderate, leading to six discontinuations, but overall tolerability aligned with the class. Food effect assessments in healthy volunteers showed no significant impact on overall exposure (AUC), though Cmax decreased by 30–40% with high-fat meals, supporting flexible administration. A renal impairment study in T2D patients (n=40) administered a single 20 mg dose, revealing modestly higher exposures in moderate to severe impairment (AUC increase up to 1.6-fold) but no dose adjustments needed, with similar tolerability to healthy subjects. These trials collectively demonstrated danuglipron's viable PK/PD profile in healthy adults and mild T2D populations, paving the way for Phase 2 efficacy investigations.

Phase 2 studies

Phase 2 clinical trials of danuglipron, an oral agonist, evaluated its efficacy and safety in patients with and , focusing on twice-daily dosing regimens. A phase 2b trial in adults with enrolled 411 participants and was designed as a randomized, double-blind, placebo-controlled study lasting 16 weeks. Doses ranged from 2.5 mg to 120 mg twice daily, administered with food and escalated as needed for higher doses. The primary endpoint was change in HbA1c from baseline, with danuglipron achieving placebo-adjusted reductions of approximately 0.8% to 1.0% across doses, reaching up to 1.16% at the 120 mg dose. Body weight reductions were also observed, up to 4.17 kg at the highest dose. Discontinuation rates due to adverse events were dose-dependent, ranging from 3% at the lowest dose to 34% at 120 mg, primarily driven by gastrointestinal tolerability issues. In parallel, a phase 2b dose-ranging trial assessed danuglipron in 626 adults with but without , using a randomized, double-blind, placebo-controlled with treatment durations of 26 or 32 weeks. Participants received escalating doses of 40 mg to 200 mg twice daily over 1- to 4-week periods. The primary endpoint of percent change in body weight from baseline showed placebo-adjusted reductions ranging from 5.0% to 12.9%, with higher doses yielding up to 13% loss at 32 weeks. Secondary measures included waist circumference reductions of 4.5 to 11.6 cm and modest improvements in plasma glucose. Across both trials, gastrointestinal adverse events were the most common, leading to high discontinuation rates of over 50% in danuglipron arms compared to around 40% with , highlighting tolerability challenges with twice-daily dosing. These findings supported the development of a once-daily modified-release , which demonstrated improved pharmacokinetic profiles and potential for better tolerability in subsequent studies.

Adverse effects

Gastrointestinal effects

Gastrointestinal adverse effects are among the most common side effects associated with danuglipron, a small-molecule (, reflecting the drug's class-specific profile. In phase 2b clinical trials, the prevalence of these effects varied by dose and formulation, with twice-daily immediate-release dosing leading to higher incidences compared to . For instance, occurred in 51% to 73% of participants across danuglipron arms, in 25% to 47%, in 10% to 30%, and abdominal discomfort (including dyspepsia and distension) in 20% to 40%. Most events were mild to moderate in severity and transient, resolving with continued treatment or dose adjustment. These effects exhibit dose- and formulation-dependency, with higher incidences observed at elevated doses (e.g., 80-200 mg BID) and shorter titration periods. In a phase 2b trial for obesity, rapid one-week escalation to 80 mg BID resulted in rates up to 62%, while a slower four-week escalation reduced this to 38%, demonstrating a 20-30% mitigation in incidence through gradual dosing. Similarly, in a trial, rose from 7% at 2.5 mg to 33% at 120 mg, underscoring the need for optimized to improve tolerability. Supportive measures, such as antiemetics, were employed in some cohorts to further alleviate symptoms, though no formal dose reductions were permitted in these studies. The gastrointestinal effects of danuglipron are mechanistically linked to GLP-1 receptor agonism, which delays gastric emptying and activates central emetic pathways in the , mimicking the physiologic responses to nutrient intake. This class effect contributes to the transient nature of symptoms, as gastrointestinal adaptation often occurs over time. Gastrointestinal events were a primary driver of treatment discontinuations, accounting for over 50% of dropouts in higher-dose groups across trials.

Hepatotoxicity

Danuglipron, an oral small-molecule , has been associated with elevations in liver enzymes, particularly (ALT) and aspartate aminotransferase (AST), observed in clinical trials. Across more than 1,400 participants in the danuglipron safety database, the overall frequency of these elevations was reported to be in line with that seen in approved , though specific incidence rates for danuglipron were not quantified beyond noting comparability to the class. In a representative example from similar oral GLP-1 candidates, such as lotiglipron, elevations occurred in approximately 6% of participants. A notable safety concern emerged from dose-optimization studies in 2025, where one asymptomatic case of potential drug-induced (DILI) was identified in a phase 1 trial. This case involved elevated liver enzymes that resolved rapidly following discontinuation of the drug, with no associated symptoms or progression to . No symptomatic has been reported with danuglipron treatment in any studies. The hepatic of danuglipron, primarily involving uptake via organic anion transporting polypeptides (OATPs) followed by contributions from (CYP) enzymes, may contribute to susceptibility for liver elevations in some individuals. This pathway underscores the potential for idiosyncratic , though risk factors beyond hepatic processing were not detailed in clinical data. Due to these liver-related signals, routine monitoring of , including ALT and AST, was recommended during danuglipron trials, consistent with practices for other oral GLP-1 candidates like lotiglipron. The profile of concerns with danuglipron mirrors challenges observed in the class, particularly for small-molecule agents undergoing hepatic clearance. The single potential case, combined with the broader context of liver enzyme elevations, underwent review by regulatory authorities including the FDA and EMA, ultimately prompting to halt development of danuglipron in April 2025 as a precautionary measure to ensure .

Development history

Discovery

Danuglipron, designated PF-06882961 during early development, was discovered in-house at through a sensitized high-throughput screen of approximately 2.8 million compounds in their library, aimed at identifying small-molecule agonists of the (GLP-1R) to overcome the limitations of injectable peptide-based therapies, such as poor oral and administration challenges. The screen utilized a BETP-sensitized cAMP accumulation , yielding a low hit rate of 0.013% and identifying 5-fluoropyrimidine-based scaffolds as starting points for optimization. Structure-based design and structure-activity relationship (SAR) studies guided the evolution of these hits into potent candidates, with key modifications including the incorporation of a at the benzimidazole 6-position to improve GLP-1R potency (EC50 = 13 nM in cell-based assays) while reducing (log D7.4 = 1.8). This process addressed the need for by enhancing and absorption without relying on structures. The compound was nominated as a development candidate around 2017. Preclinical efficacy was evaluated primarily in non-human due to species-specific differences in GLP-1R ; PF-06882961 showed no glucose-lowering effects in models lacking the critical residue at position 33. In cynomolgus monkeys, however, oral dosing at 30 mg/kg reduced postprandial glucose excursions by approximately 25% during an oral and decreased 24-hour cumulative food intake by about 30% at 3 mg/kg. Chronic oral administration at 10 mg/kg twice daily for 4 weeks resulted in dose-dependent body weight reductions of up to 5%. Oral was favorable and dose-dependent, reaching 11% in rats at 5 mg/kg and 39% at 100 mg/kg, and 5-9% in monkeys. Optimization milestones included refinements for biased , prioritizing G-protein-coupled cAMP signaling over β-arrestin (bias factor ≈ 10), which aimed to preserve glycemic benefits while potentially reducing side effects such as emesis. These advancements supported the filing of an (IND) application in 2017, paving the way for initial human evaluations. secured through patents covering the chemical structure and pharmaceutical formulations, including WO 2018/109607 (filed December 8, 2017) and WO 2019/239371 (filed June 7, 2019).

Discontinuation

On April 14, 2025, Pfizer announced the discontinuation of the clinical development program for danuglipron, an oral glucagon-like peptide-1 (GLP-1) receptor agonist intended for obesity and type 2 diabetes treatment. The decision followed a comprehensive review of cumulative safety data from clinical trials, which revealed unpredictable elevations in liver enzymes, including a single case of drug-induced liver injury (DILI) that resolved rapidly upon drug cessation. This halt prevented initiation of Phase 3 trials, marking the end of advancement for the once-daily formulation that had shown promise in earlier studies. The timeline of danuglipron's development culminated in this termination after positive Phase 2b results in 2023, which supported progression to a once-daily dosing regimen optimized in 2024. However, emerging safety signals from ongoing studies, particularly related to , prompted to weigh the drug's efficacy against these risks, ultimately deeming further investment untenable. This choice echoed challenges with 's related compound, lotiglipron, which was discontinued in June 2023 due to similar liver enzyme elevations observed in early testing. In the wake of the announcement, shifted focus to alternative GLP-1 candidates within its pipeline, emphasizing programs with more favorable safety profiles. The discontinuation underscored persistent hurdles in developing oral formulations for the market, potentially slowing in non-injectable GLP-1 therapies amid from established injectable options. In June 2025, results from a phase 2b study were published, reporting significant reductions in HbA1c and body weight but higher discontinuation rates due to gastrointestinal adverse events.

References

  1. https://pmc.ncbi.nlm.nih.gov/articles/PMC10107991/
  2. https://pmc.ncbi.nlm.nih.gov/articles/PMC9234956/
  3. https://pmc.ncbi.nlm.nih.gov/articles/PMC10203889/
  4. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-advances-development-once-daily-formulation-oral-glp
  5. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-provides-update-oral-glp-1-receptor-agonist
  6. https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01856
  7. https://www.sciencedirect.com/science/article/pii/S0753332224008497
  8. https://www.nature.com/articles/s41392-024-01931-z
  9. https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1431292/full
  10. https://accp1.onlinelibrary.wiley.com/doi/10.1002/jcph.2371
  11. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2805054
  12. https://pubmed.ncbi.nlm.nih.gov/37213102/
  13. https://academic.oup.com/edrv/advance-article/doi/10.1210/endrev/bnaf036/8276515
  14. https://bhm.scholasticahq.com/article/132255-current-insights-advantages-and-challenges-of-small-molecule-glucagon-like-peptide-1-receptor-agonists-a-scoping-review
  15. https://dom-pubs.onlinelibrary.wiley.com/doi/full/10.1111/dom.16534
  16. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-announces-topline-phase-2b-results-oral-glp-1r
  17. https://pubmed.ncbi.nlm.nih.gov/39892489/
  18. https://clinicaltrials.gov/study/NCT03309241
  19. https://www.nature.com/articles/s41591-021-01391-w
  20. https://pubmed.ncbi.nlm.nih.gov/37840155
  21. https://www.cnbc.com/2025/04/14/pfizer-scraps-daily-weight-loss-pill-danuglipron.html
  22. https://pmc.ncbi.nlm.nih.gov/articles/PMC11618248/
  23. https://medcitynews.com/2025/04/pfizer-oral-glp-1-obesity-weight-loss-danuglipron-liver-enzymes-pfe/
  24. https://accp1.onlinelibrary.wiley.com/doi/pdf/10.1002/jcph.2371
  25. https://www.mdpi.com/2218-0532/93/2/26
  26. https://www.statnews.com/2025/04/14/pfizer-discontinue-danuglipron-glp-1-obesity-liver-toxicity/
  27. https://patents.google.com/patent/WO2018109607A1/en
  28. https://patents.google.com/patent/WO2019239371A1/en
  29. https://www.reuters.com/business/healthcare-pharmaceuticals/pfizer-ends-development-weight-loss-pill-danuglipron-2025-04-14/
  30. https://pmc.ncbi.nlm.nih.gov/articles/PMC12326921/
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