2. Academic Validation
  3. 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

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

  • J Med Chem. 2022 Oct 27;65(20):13946-13966. doi: 10.1021/acs.jmedchem.2c01192.
Angelica Artasensi 1,  Andrea Angeli 2,  Carmen Lammi 1,  Carlotta Bollati 1,  Silvia Gervasoni 1 3,  Giovanna Baron 1,  Rosanna Matucci 4,  Claudiu T Supuran 2,  Giulio Vistoli 1,  Laura Fumagalli 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences "DISFARM", Università degli Studi di Milano, via Mangiagalli 25, I-20133 Milan, Italy.
  • 2 Department of Pharmaceutical Sciences "NEUROFARBA", University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
  • 3 Department of Physics, Citt. Universitaria, University of Cagliari, I-09042 Cagliari, Monserrato, Italy.
  • 4 Department of Pharmacology and Toxicology "NEUROFARBA", University of Florence, Viale Pieraccini 6, 50134 Florence, Italy.
PMID: 36201615 DOI: 10.1021/acs.jmedchem.2c01192
Abstract

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.

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