Discovery of a Potent and Highly Selective Dipeptidyl Peptidase IV and Carbonic Anhydrase Inhibitor as “Antidiabesity” Agents Based on Repurposing and Morphing of WB-4101

The
management of patients with type 2 diabetes mellitus (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 (DPP IV) and
carbonic anhydrases (CAs II and V) in T2DM and in the weight loss,
we report a new class of multitarget ligands targeting the mentioned
enzymes. We started from the known α1-AR inhibitor
WB-4101, which was progressively modified through a tailored morphing
strategy to optimize the potency of DPP IV and CAs while losing the
adrenergic activity. The obtained compound 12 shows a
satisfactory DPP IV inhibition with a good selectivity CA profile
(DPP IV IC50: 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 a lead compound in this novel class of multitarget
ligands.