Synthesis and Characterization of New V1A Antagonist Compounds: The Separation of Four Atropisomeric Stereoisomers

A new class of selective vasopressin receptor 1A (V-1A) antagonists was identified, where methyl-scan was performed around the benzene ring of the 5-hydroxy-triazolobenzazepine core. This led to the synthesis of two 10-methyl derivatives, each possessing a chiral axis and a stereogenic center. The four atropisomeric stereoisomers (involving two enantiomer pairs and atropisomeric diastereomers) could be successfully isolated and spectroscopically characterized. According to the in vitro pharmacological profiles of the compounds, the human V-1A receptor has a strong preference toward the isomers having an aR axial chirality, the most active isomer being the aR,5S isomer. Furthermore, the structure-activity relationships obtained for the isomers and for the newly synthesized analogues could be tentatively explained by an in silico study.

Automated summary

A new class of selective vasopressin receptor 1A (V-1A) antagonists has been identified, with the synthesis of four atropisomeric stereoisomers characterized by chiral axis and a stereogenic center. In vitro pharmacological profiles show that the human V-1A receptor strongly prefers the isomers with aR axial chirality, with the most active isomer being the aR,5S form. The structure-activity relationships for the isomers and newly synthesized analogues could be tentatively explained by an in silico study.