Data di Pubblicazione:
2021
Citazione:
Novel potential DPP IV/CA II inhibitors for treatment of type 2 diabetes / A. Artasensi, A. Angeli, C. Lammi, C. Supuran, G. Vistoli, L. Fumagalli. ((Intervento presentato al 27. convegno Congresso Nazionale SCI tenutosi a online nel 2021.
Abstract:
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.
Tipologia IRIS:
14 - Intervento a convegno non pubblicato
Elenco autori:
A. Artasensi, A. Angeli, C. Lammi, C. Supuran, G. Vistoli, L. Fumagalli
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