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

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.