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Isolated Pancreatic Islet Treatment and Apoptosis Measurement
Published on: May 2, 2025
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Selective and Orally Bioavailable Dipeptidyl Peptidase 9 Inhibitors with Potent Pyroptosis Induction Properties
Nicolò Filippi1, Kathleen Mertens2, Joni De Loose2
1Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, Wilrijk 2610, Belgium.
Journal of Medicinal Chemistry
|October 29, 2025
Summary
Novel dipeptidyl peptidase 9 (DPP9) inhibitors show potent pyroptosis induction in leukemia and HIV-1-infected cells. Compound 6e exhibits excellent oral bioavailability and half-life in rats, offering potential therapeutic applications.
Area of Science:
- Biochemistry
- Pharmacology
- Immunology
Background:
- Dipeptidyl peptidase 9 (DPP9) regulates pyroptosis in leukocytes.
- DPP9 inhibitors show promise in treating acute myeloid leukemia (AML) and HIV-1 infection.
Purpose of the Study:
- To report structure-activity relationship data for novel low nanomolar DPP9 inhibitors.
- To evaluate pyroptosis-inducing potency, selectivity, and pharmacokinetic properties of these inhibitors.
Main Methods:
- Synthesis and characterization of novel DPP9 inhibitors.
- Assessment of pyroptosis induction in AML cells and HIV-1-infected T-lymphocytes.
- Evaluation of DPP9 selectivity against DPP8, DPP4, and other peptidases.
- Pharmacokinetic studies of lead compound 6e in rats.
Main Results:
- Novel DPP9 inhibitors demonstrated unprecedented pyroptosis-inducing potency and kinetics.
- Compound 6e exhibited substantial DPP9-to-DPP8 selectivity and full selectivity over DPP4.
- Compound 6e showed high oral bioavailability and long in vivo and microsomal half-life in rats.
- Investigated pyroptosis induction potential in HIV-1-infected T-lymphocytes.
Conclusions:
- These novel DPP9 inhibitors possess significant therapeutic potential for AML and HIV-1.
- Compound 6e is a promising candidate for further drug development due to its favorable pharmacokinetic profile.
- The developed compounds serve as valuable research tools for exploring DPP9's role in disease.
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