Novel potential DPP IV/CA II inhibitors for treatment of type 2 diabetes

Diabetes syndrome is characterized by high blood sugar levels, which trigger a pro-inflammatory response that causes micro-vascular damage and leads to serious chronic complications such as blindness, renal failure and diabetes-accelerated atherosclerosis [1,2]. Furthermore, several major enzymes are abnormally expressed or show anomalous activity in this state of metabolic disturbance, so they might be interesting targets in drug discovery. Hence, the development of multitarget drugs, which could reduce hyperglycemia and slow down the progression of complications, may offer a valuable therapeutic option. In order to find new therapeutic strategies, repurposing and morphing approaches were applied on WB-4101, a well-known adrenergic ligand. Repurposing [3] could minimize the risk of failure in future late-stage clinical trials due to toxicity, while morphing approach could allow to introduce/modulate the activity towards old and new targets, to retain satisfactory drug likeness properties and to avoid issues in the patent landscape. Repurposing studies found out that WB-4101 can conveniently fit the binding pockets of two enzymes, namely Dipeptidyl Peptidase IV (DPP IV) and Carbonic Anhydrase II (CA II) involved in Type 2 Diabetes Mellitus (T2D), while failing to stabilize all required interactions. Indeed, WB-4101 lacks a moiety able to interact with a key arginine residue in the DPP IV pocket and with the zinc ion of the CA II. Our class of compounds were designed with the purpose of satisfying both these needs by inserting a sulfonamide function, which is a well-known chelating group for the Zinc ion and can be seen as a valid bioisostere of the carboxyl group to interact with the arginine [4]. In addition, this moiety was inserted in para position on the phenoxy ring based on previous investigations, which demonstrated that this substitution abrogates or strongly reduces the adrenergic affinity. Computational and pharmacological investigations were performed also on CA V, a mitochondrial carbonic anhydrase isoform involved in glucose metabolism [5]. Here, we report the investigation of several derivatives for expanding the structure activity relationship (SAR) of this new class of compounds and to further improve the rational ligand design. [1] Bawa P, Pradeep P, Kumar P, Choonara YE, Modi G, Pillay V. Drug Discov. Today, 2016, 21, 1886. [2] Artasensi, A.; Pedretti, A.; Vistoli, G.; Fumagalli, L. Molecules, 2020, 25, 1987. [3] Ramsay, R. R., Popovic-Nikolic, M. R., Nikolic, K., Uliassi, E., & Bolognesi, M. L. Clin Transl Med, 2018, 7:3. [4] Arabi AA. Routes to drug design via bioisosterism of carboxyl and sulfonamide groups. Future Med Chem. 2017, 9, 2167. [5] Supuran CT, Di Fiore A, De Simone G. Expert Opin Emerg Drugs. 2008, 13(2), 383.