Investigations on the 4‑Quinolone-3-carboxylic Acid Motif. 7. Synthesis and Pharmacological Evaluation of 4‑Quinolone-3-carboxamides and 4‑Hydroxy-2-quinolone-3-carboxamides as High Affinity Cannabinoid Receptor 2 (CB2R) Ligands with Improved Aqueous Solubility

4-Quinolone-3-carboxamide derivatives
have long been recognized
as potent and selective cannabinoid type-2 receptor (CB2R) ligands.
With the aim to improve their physicochemical properties, basically
aqueous solubility, two different approaches were followed, entailing
the substitution of the alkyl chain with a basic replacement or scaffold
modification to 4-hydroxy-2-quinolone structure. According to the
first approach, compound 6d was obtained, showing slightly
reduced receptor affinity (Ki = 60 nM)
compared to the lead compound 4 (0.8 nM) but greatly
enhanced solubility (400–3400 times depending on the pH of
the medium). On the other hand, shifting from 4-quinolone to 4-hydroxy-2-quinolone
structure enabled the discovery of a novel class of CB2R ligands,
such as 7b and 7c, characterized by Ki < 1 nM and selectivity index [SI = Ki(CB1R)/Ki(CB2R)]
> 1300. At pH 7.4, compound 7c resulted by 100-fold
more
soluble than 4.