Design of α7 nicotinic acetylcholine receptor ligands using the (het)Aryl-1,2,3-triazole core: Synthesis, in vitro evaluation and SAR studies

• Published in: European journal of medicinal chemistry 2016-01, Vol.107, p.153-164
• Main Authors: Ouach, Aziz, Pin, Frederic, Bertrand, Emilie, Vercouillie, Johnny, Gulhan, Zuhal, Mothes, Céline, Deloye, Jean-Bernard, Guilloteau, Denis, Suzenet, Franck, Chalon, Sylvie, Routier, Sylvain
• Format: Article
• Language: English
• Subjects: Alpha 7 nicotinic acetylcholine receptors; alpha7 Nicotinic Acetylcholine Receptor - agonists; alpha7 Nicotinic Acetylcholine Receptor - metabolism; Animals; Chemistry Techniques, Synthetic; Click Chemistry; Drug Design; Drug Evaluation, Preclinical - methods; Humans; Inhibitory Concentration 50; In vitro evaluation; Ligands; Quinuclidine; Rats; Receptors, Nicotinic - metabolism; SAR; Serotonin 5-HT3 Receptor Antagonists - chemistry; Serotonin 5-HT3 Receptor Antagonists - pharmacology; Structure-Activity Relationship; Triazole synthesis; Triazoles - chemistry; Triazoles - pharmacology; Tropane
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.11.001

We report here the synthesis of a large library of 1,2,3-triazole derivatives which were in vitro tested as α7 nAchR ligands. The SAR study revealed that several crucial factors are involved in the affinity of these compounds for α7 nAchR such as a (R) quinuclidine configuration and a mono C-3 quinuclidine substitution. The triazole ring was substituted by a phenyl ring bearing small OMe/CH2F groups or fluorine atom and by several heterocycles such as thiophenes, furanes, benzothiophenes or benzofuranes. Among the 30 derivatives tested, the two derivatives 10 and 39 with Ki in the nanomolar range were identified (2.3 and 3 nM respectively). They exhibited a strict selectivity toward the α4β2 nicotinic receptor (up to 1 μM) but interacted with the 5HT3 receptors with Ki around 3 nM. Synthesis, SAR studies and a full description of the derivatives are reported. [Display omitted] •30 new potent alpha 7 nAChR ligand synthesized derivatives synthesized.•2 identified leads exhibited a strong affinity (Ki = 2.3 and 3 nM).•Leads exhibit strict selectivity toward the α4β2 nicotinic receptor.•Leads induced a 5HT3 receptors Inhibition with Ki around 3 nM.•Rational design, synthesis, SAR are depicted.