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Novel Difluorocyclobutyl Derivatives as Potent Glucagon-Like Peptide-1 Receptor Agonists with Reduced hERG Inhibitory Activity

17 June 2025

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Research conducted at the College of Ocean, Zhejiang University, by Professor Wanjing Ding and Professor Zhongjun Ma has led to significant advances in pharmaceutical development.

Professor Ding, a distinguished postdoctoral researcher and visiting scholar at the University of Southern California, specializes in marine natural product anti-tumour pharmacology. Her research portfolio includes leadership of several prestigious grants, including the National Natural Science Youth Fund, and numerous publications in high-impact journals such as JMC, EJMC, and Nature Product Research.

Professor Ma, with postdoctoral experience from the University of British Columbia and Purdue University, has made substantial contributions to marine drug development, with over 90 SCI publications and 40+ patents. His research leadership extends to major projects funded by the National Natural Science Foundation and the Zhejiang Provincial Science and Technology Department.

Initial studies revealed that Danuglipron demonstrates significant potential in cAMP stimulation, despite exhibiting moderate hERG inhibition (IC₅₀ = 4.3 μM). Through computer-aided drug design (CADD), researchers developed novel difluorocyclobutyl derivatives using Danuglipron as the lead compound, specifically targeting reduced hERG channel inhibition.

The molecular design strategy involved a three-part structural modification of Danuglipron (Figure 1). The researchers implemented key structural changes:

· Replacement of piperidine with 4-oxidaneylpiperidine in Part B to minimize hERG inhibition, and

· Substitution of the benzimidazole scaffold in Part C with hexavalent heterocyclic imidazole and thienoimidazole.

Two compound series were systematically designed to investigate structure-activity relationships (SAR), focusing on substituent variations on the benzene ring and linker1 in Part A.

Figure 1. Molecular Design Strategy and Structure-Activity Relationship Analysis for Molecular Docking.

The synthetic pathways for three critical intermediates are illustrated below (Figures 2-4):

Figure 2. Synthetic Route to Intermediate A

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Figure 3. Synthetic Route to Intermediate B

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Figure 4. Synthetic Route to Intermediate C

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This investigation identified a novel class of GLP-1R agonists characterized by enhanced activity, selectivity, and pharmacokinetic properties, coupled with reduced hERG channel inhibition and decreased cardiac toxicity potential.

Notably, Compound 73 exhibited superior pathway selectivity and lower β-Arrestin agonist activity compared to Danuglipron, demonstrating robust glycemic control. These properties position it as a promising therapeutic candidate for Type 2 Diabetes Mellitus (T2DM) and obesity treatment.

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To facilitate further research in this area, AmBeed offers a comprehensive range of high-purity building blocks and reagents essential for these synthetic pathways.

Additionally, AmBeed provides specialized custom synthesis services, supporting research initiatives across pharmaceutical companies, biotechnology firms, Contract Research Organizations (CROs), and academic institutions.

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References

[1]Miao L, Lou J, Xu S, et al. Discovery of New Difluorocyclobutyl Derivatives as Effective Glucagon-Like Peptide-1 Receptor Agonists with Reduced hERG Inhibitory Activities[J]. Journal of Medicinal Chemistry, 2025, 68(7): 7662-7692.

[2]Tamura T, Noda H, Joyashiki E, et al. Identification of an orally active small-molecule PTHR1 agonist for the treatment of hypoparathyroidism[J]. Nature Communications, 2016, 7(1): 13384.

[3]Hoang H N, Song K, Hill T A, et al. Short hydrophobic peptides with cyclic constraints are potent glucagon-like peptide-1 receptor (GLP-1R) agonists[J]. Journal of Medicinal Chemistry, 2015, 58(9): 4080-4085.

[4]Saxena A R, Gorman D N, Esquejo R M, et al. Danuglipron (PF-06882961) in type 2 diabetes: a randomized, placebo-controlled, multiple ascending-dose phase 1 trial[J]. Nature Medicine, 2021, 27(6): 1079-1087.

[5]Sanguinetti M C, Tristani-Firouzi M. hERG potassium channels and cardiac arrhythmia[J]. Nature, 2006, 440(7083): 463-469.

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