Structure–activity relationships of N-substituted 4-(trifluoromethoxy)benzamidines with affinity for GluN2B-containing NMDA receptors

• Published in: Bioorganic & medicinal chemistry letters 2014-02, Vol.24 (3), p.828-830
• Main Authors: Beinat, Corinne, Banister, Samuel D., Hoban, Jane, Tsanaktsidis, John, Metaxas, Athanasios, Windhorst, Albert D., Kassiou, Michael
• Format: Article
• Language: English
• Subjects: Amidine; Benzamidines - chemical synthesis; Benzamidines - chemistry; Benzamidines - pharmacology; CNS; Cyclization; Fluorine - chemistry; GluN2B; Glutamates - chemistry; Glutamates - metabolism; NMDA; Polycyclic Compounds - chemical synthesis; Polycyclic Compounds - chemistry; Protein Binding - drug effects; Receptors, N-Methyl-D-Aspartate - chemistry; Receptors, N-Methyl-D-Aspartate - metabolism; Structure-Activity Relationship; Structure–activity relationships
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.12.087

Our positive findings relating to the use of BZAD01 (6) in the treatment of PD has stimulated the further structure affinity relationship exploration of this compound. The synthesis and binding affinities of ligands exploring benzyl ring substitution and polycyclic moiety incorporation is reported. GluN2B subtype-selective NMDA antagonists represent promising therapeutic targets for the symptomatic treatment of multiple CNS pathologies. A series of N-benzyl substituted benzamidines were synthesised and the benzyl ring was further replaced with various polycyclic moieties. Compounds were evaluated for activity at GluN2B containing NMDA receptors where analogues 9, 12, 16 and 18 were the most potent of the series, replacement of the benzyl ring with polycycles resulted in a complete loss of activity.