Highly potent dipeptidyl peptidase 8/9 (DPP8/9) inhibitors designed via relative binding free energy calculations

  • Eur J Med Chem. 2025 Nov 5:297:117913. doi: 10.1016/j.ejmech.2025.117913.
Vanesa Nozal  1 ,  Olivier Beyens  2 ,  Sarah Peeters  2 ,  Adrian Fabisiak  2 ,  Koen Augustyns  2 ,  Ingrid De Meester  3 ,  Pieter Van Der Veken  2 ,  Hans De Winter  4
Affiliations
  • 1. Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, 2610 Wilrijk, Belgium; Institut Químic de Sarrià (IQS), Universitat Ramon Llull, 08017, Barcelona, Spain. Electronic address: [email protected].
  • 2. Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, 2610 Wilrijk, Belgium.
  • 3. Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, 2610 Wilrijk, Belgium.
  • 4. Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, 2610 Wilrijk, Belgium. Electronic address: [email protected].
PMID: 40609224 DOI: 10.1016/j.ejmech.2025.117913
Abstract

Dipeptidyl peptidases (DPP) 8 and 9 are emerging enzymatic drug targets with suggested applications in acute myeloid leukaemia and HIV Infection, among Others. In this work, we optimised a well-known reference DPP8/9 inhibitor named 1G244, using relative binding free energy calculations. An initial retrospective, computational analysis of experimental structure-activity data of 1G244 and close structural analogues, guided the subsequent prospective design of novel inhibitors derived from the reference scaffold. Synthesis of the proposed compounds - together with in vitro evaluation and initial pharmacokinetic and pharmacodynamic studies - are presented and discussed. As a result, we present the optimization of 1G244 in a new family of potent piperidine based DPP8/9 inhibitors. Finally, we report for lead compound 21 and reference 1G244 the cardiac channel affinity which must be carefully considered when using these molecules as a tool to further clarify the role of DPP8 and DPP9 in cellular physiology.

Keywords
Dipeptidyl peptidase; Free energy perturbations; Inhibitor; hERG affinity.
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