Discovery of a potent and highly selective Dipeptidyl Peptidase IV and Carbonic Anhydrase inhibitor as “antidiabesity” agent based on repurposing and morphing of WB-4101

The management of patients with type 2 diabetes (T2DM) is shifting from cardio-centric to weight-centric or, even better, adipose-centric treatments. Considering the downsides of multidrug therapies and the relevance of Dipeptidyl Peptidase IV (DPPIV) and Carbonic Anhydrases (CA II and V) in T2DM and in the weighting loss, we report a new class of multitarget ligands targeting the mentioned enzymes. We started from the known α 1 -AR inhibitor, WB-4101, which was pro- gressively modified through a tailored morphing strategy to optimize the potency on DPP IV and CAs, while losing the adren- ergic activity. The obtained compound 12 shows a satisfying DPP IV inhibition with a good selectivity CAs profile (DPPIV IC 50: 0.0490 μM; CA II Ki 0.2615 μM; CA VA Ki 0.0941 μM; CA VB Ki 0.0428 μM). Furthermore, its DPP IV inhibitory activity in Caco- 2 and its acceptable pre-ADME/Tox profile indicate it as lead compound of this novel class of multitarget ligands.