Investigations on the 4-Quinolone-3-Carboxylic Acid Motif Part 5: Modulation of the Physicochemical Profile of a Set of Potent and Selective Cannabinoid-2 Receptor Ligands through a Bioisosteric Approach

• Published in: ChemMedChem 2012-05, Vol.7 (5), p.920-934
• Main Authors: Mugnaini, Claudia, Nocerino, Stefania, Pedani, Valentina, Pasquini, Serena, Tafi, Andrea, De Chiaro, Maria, Bellucci, Luca, Valoti, Massimo, Guida, Francesca, Luongo, Livio, Dragoni, Stefania, Ligresti, Alessia, Rosenberg, Avraham, Bolognini, Daniele, Cascio, Maria Grazia, Pertwee, Roger G., Moaddel, Ruin, Maione, Sabatino, Di Marzo, Vincenzo, Corelli, Federico
• Format: Article
• Language: English
• Subjects: 4-Quinolones - chemistry; Animals; bioisosteres; cannabinoids; Carboxylic Acids - chemistry; Cell Line, Tumor; CHO Cells; Chromatography, High Pressure Liquid; Computer Simulation; Cricetinae; Cricetulus; Humans; Ligands; Lipids - chemistry; Mice; Models, Molecular; Molecular Structure; Protein Structure, Tertiary; quinolones; Receptor, Cannabinoid, CB2 - agonists; receptors; Solubility; Structure-Activity Relationship; structure-activity relationships
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201100573

Three heterocyclic systems were selected as potential bioisosteres of the amide linker for a series of 1,6‐disubstituted‐4‐quinolone‐3‐carboxamides, which are potent and selective CB2 ligands that exhibit poor water solubility, with the aim of improving their physicochemical profile and also of clarifying properties of importance for amide bond mimicry. Among the newly synthesized compounds, a 1,2,3‐triazole derivative (1‐(adamantan‐1‐yl)‐4‐[6‐(furan‐2‐yl)‐1,4‐dihydro‐4‐oxo‐1‐pentylquinolin‐3‐yl]‐1H‐1,2,3‐triazole) emerged as the most promising in terms of both physicochemical and pharmacodynamic properties. When assayed in vitro, this derivative exhibited inverse agonist activity, whereas, in the formalin test in mice, it produced analgesic effects antagonized by a well‐established inverse agonist. Metabolic studies allowed the identification of a side chain hydroxylated derivative as its only metabolite, which, in its racemic form, still showed appreciable CB2 selectivity, but was 150‐fold less potent than the parent compound. Less psycho more active! Cannabinoid receptor type 2 (CB2)‐selective agonists have potential as therapeutics for the treatment of pain, however, poor selectivity over CB1 has hampered the development. Here, the modulation of physicochemical properties of CB2 ligands through a simple bioisosteric approach was performed without significant loss of receptor affinity in an attempt to obtain potent leads with desirable drug‐like properties.