Discovery of new SCH 39166 analogs as potent and selective dopamine D1 receptor antagonists

A series of novel dopamine D1 antagonists derived from functionalization of the D-ring of SCH 39166 were prepared. A number of these compounds displayed subnanomolar D1 activity and more than 1000-fold selectivity over D2. We found C-3 derivatization afforded compounds with superior overall profile in comparison to the C-2 and C-4 derivatization. A number of highly potent D1 antagonists were discovered which have excellent selectivity over other dopamine receptors and improved PK profile compared to SCH 39166.

The D-ring functionalization of SCH 39166 is described. Compound 17c was discovered to have subnanomolar D1 activity and nearly 10-fold improvement of selectivity over D2 compared to SCH 39166. It also showed a significant improvement of PK profile.Figure optionsDownload as PowerPoint slide