Remote functionalization of SCH 39166: Discovery of potent and selective benzazepine dopamine D1 receptor antagonists

A series of novel benzazepine derived dopamine D1 antagonists have been discovered. These compounds are highly potent at D1 and showed excellent selectivity over D2 and D4 receptors. SAR studies revealed that a variety of functional groups are tolerated on the D-ring of known tetracyclic benzazepine analog 2, SCH 39166, leading to compounds with nanomolar potency at D1 and good selectivity over D2-like receptors.

Graphical abstractA series of highly potent dopamine D1 antagonists have been discovered. All compounds showed excellent selectivity over other dopaminergic receptors. Compound 8j showed a modestly improved PK profile than SCH 39166.Figure optionsDownload full-size imageDownload as PowerPoint slide