Repurposing the amino-3,5-dicyanopyridine scaffold from adenosine receptor ligands to carbonic anhydrase activators

We are repurposing a set of imidazole-containing amino-3,5-dicyanopyridines, previously reported as Adenosine Receptor ligands, in the role of activators of human-expressed Carbonic Anhydrase isoenzymes (hCA I, II, VA, and VII) considered relevant to controlling brain functions. Our focus has been to identify new Carbonic Anhydrase activators (CAAs) as pharmacological tools useful to investigate the CA role in psychiatric and neurodegenerative disorders. All tested compounds were inactive at hCA II, highlighting a trend similar to that of the reference activator histamine. On the contrary, most of them showed different activation profiles at the Other CAs tested. In particular, while compounds 13 and 24 had the lowest K_A values at hCA VII (K_A = 0.8 μM) and I (K_A = 0.7 μM), respectively, derivatives 14 and 17 displayed the most effective and balanced activation profile at hCA I, VA, and VII, with K_A values in the low micromolar range. The binding mode of compound 14 was investigated in silico using X-ray solved (hCA I and VII) and homology built (hCA VA) structures. Focusing our attention on drug-like compounds to find new pharmacological tools, the ADME properties of all derivatives were in silico calculated to investigate their drug-like behavior. Compound 17 emerged as a candidate, as it showed high oral availability and permeability of the gut-blood barrier, together with a good potential to cross the BBB.

Amino-3,5-dicyanopyridines; Carbonic anhydrase activators; Cognition-related disorders; Memory impairment diseases; Repurposing approach.