Danuglipron (PF-06882961) in type 2 diabetes: a randomized, placebo-controlled, multiple ascending-dose phase 1 trial

Saxena, Akshar; Gorman, Donal; Esquejo, Ryan M.; Bergman, Arthur; Chidsey, Kristin; Buckeridge, Clare; Griffith, David A.; Kim, Albert M.

doi:10.1038/s41591-021-01391-w

Cited by 92 publications

(115 citation statements)

References 29 publications

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“…A Phase 1 study with danuglipron has been recently completed, showing favorable efficacy and safety of multiple doses of danuglipron over 4 weeks of treatment in participants with T2DM. 52 Longer Phase 2 studies of danuglipron will need to be conducted in subjects with T2DM to determine optimal dosing for sustained glycemic control.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, danuglipron demonstrated beneficial changes during a recently reported multiple-dose study in volunteers with T2DM. 52 This research had a number of strengths, including the demonstration that a PAM-sensitized SA could identify very weak hits for a challenging GPCR target. The iterative process of discovery and development of danuglipron from weak hits through to demonstration of the compound’s bioavailability in humans is described, highlighting the multiple considerations taken when designing and selecting an optimal drug candidate.…”

Section: Discussionmentioning

confidence: 99%

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A Small-Molecule Oral Agonist of the Human Glucagon-like Peptide-1 Receptor

et al. 2022

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Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited because they require injection. Herein, we describe the discovery of the orally bioavailable, small-molecule, GLP-1R agonist PF-06882961 (danuglipron). A sensitized high-throughput screen was used to identify 5-fluoropyrimidine-based GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nanomolar potency. Incorporation of a carboxylic acid moiety provided considerable GLP-1R potency gains with improved off-target pharmacology and reduced metabolic clearance, ultimately resulting in the identification of danuglipron. Danuglipron increased insulin levels in primates but not rodents, which was explained by receptor mutagensis studies and a cryogenic electron microscope structure that revealed a binding pocket requiring a primate-specific tryptophan 33 residue. Oral administration of danuglipron to healthy humans produced dose-proportional increases in systemic exposure (NCT03309241). This opens an opportunity for oral small-molecule therapies that target the well-validated GLP-1R for metabolic health.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Small-Molecule Oral Agonist of the Human Glucagon-like Peptide-1 Receptor

et al. 2022

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“…Diabetes mellitus (DM), characterised by chronic hyperglycaemia, has become a serious globalised problem threatening human health 1 . It is estimated that more than 460 million people have been suffering from DM with the number of people with DM reaching more than 570 million by 2030 2 . In the light of the causative mechanism, diabetes can be categorised into four classes as follows: type-1 diabetes (T1D), type-2 diabetes (T2D), gestational diabetes (GD) and specific types of diabetes 3 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and bioactivities evaluation of oleanolic acid oxime ester derivatives as α-glucosidase and α-amylase inhibitors

Deng

Zheng

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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Different oleanolic acid (OA) oxime ester derivatives ( 3a - 3t ) were designed and synthesised to develop inhibitors against α -glucosidase and α -amylase. All the synthesised OA derivatives were evaluated against α -glucosidase and α -amylase in vitro. Among them, compound 3a showed the highest α -glucosidase inhibition with an IC 50 of 0.35 µM, which was ∼1900 times stronger than that of acarbose, meanwhile compound 3f exhibited the highest α -amylase inhibitory with an IC 50 of 3.80 µM that was ∼26 times higher than that of acarbose. The inhibition kinetic studies showed that the inhibitory mechanism of compounds 3a and 3f were reversible and mixed types towards α -glucosidase and α -amylase, respectively. Molecular docking studies analysed the interaction between compound and two enzymes, respectively. Furthermore, cytotoxicity evaluation assay demonstrated a high level of safety profile of compounds 3a and 3f against 3T3-L1 and HepG2 cells. Highlights Oleanolic acid oxime ester derivatives ( 3a–3t ) were synthesised and screened against α-glucosidase and α-amylase. Compound 3a showed the highest α-glucosidase inhibitory with IC50 of 0.35 µM. Compound 3f presented the highest α-amylase inhibitory with IC50 of 3.80 µM. Kinetic studies and in silico studies analysed the binding between compounds and α-glucosidase or α-amylase.

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“…It is conservatively estimated that T2DM will affect approximately 500 million people worldwide by 2030, and the mortality rate for the disease and its associated complications is one death every 6 s as of now ( Kumar et al, 2021 ). The effective way to reduce blood glucose levels in the treatment and prevention of T2DM and its complications is the clinical use of oral hypoglycemic agents such as sulfonylureas ( Liang et al, 2020 ; Ling et al, 2021 ), biguanides ( Zheng T.-L. et al, 2021 ; Kathuria et al, 2021 ), thiazolidinedione-derived drugs ( Long et al, 2021 ; Liu et al, 2021 ), dipeptidyl-peptidase IV inhibitors ( Carullo et al, 2021 ; Cheng et al, 2022 ), α -glucosidase inhibitors ( Hossain et al, 2020 ), sodium-glucose cotransporter-2 inhibitors ( Provenzano et al, 2021 ), and glucagon-like peptide-1 (GLP-1) receptor agonists ( Furer et al, 2021 ; Saxena et al, 2021 ). Among these, α -glucosidase inhibitors are widely used as clinical drugs including acarbose, voglibose, miglitol, and emiglitate, and there are reports on α -amylase inhibitors derived from the natural product.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Benzylidene Analogs of Oleanolic Acid as Potential α-Glucosidase and α-Amylase Inhibitors

Lin

Zhang

et al. 2022

Front. Chem.

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A series of benzylidene analogs of oleanolic acid 4a∼4s were synthesized and assessed for their α-glucosidase and α-amylase inhibitory activities. The results presented that all synthesized analogs exhibited excellent-to-moderate inhibitory effects on α-glucosidase and α-amylase. Analog 4i showed the highest α-glucosidase inhibition (IC50: 0.40 μM), and analog 4o presented the strongest α-amylase inhibition (IC50: 9.59 μM). Inhibition kinetics results showed that analogs 4i and 4o were reversible and mixed-type inhibitors against α-glucosidase and α-amylase, respectively. Simulation docking results demonstrated the interaction between analogs and two enzymes. Moreover, analogs 4i and 4o showed a high level of safety against 3T3-L1 and HepG2 cells.

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Danuglipron (PF-06882961) in type 2 diabetes: a randomized, placebo-controlled, multiple ascending-dose phase 1 trial

Cited by 92 publications

References 29 publications

A Small-Molecule Oral Agonist of the Human Glucagon-like Peptide-1 Receptor

A Small-Molecule Oral Agonist of the Human Glucagon-like Peptide-1 Receptor

Synthesis and bioactivities evaluation of oleanolic acid oxime ester derivatives as α-glucosidase and α-amylase inhibitors

Synthesis of Benzylidene Analogs of Oleanolic Acid as Potential α-Glucosidase and α-Amylase Inhibitors

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