Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists

Starting from the potent and selective but poorly brain penetrant 5-HT6 receptor antagonist SB-271046, a successful strategy for improving brain penetration was adopted involving conformational constraint with concomitant reduction in hydrogen bond count. This provided a series of bicyclic heteroarylpiperazines with high 5-HT6 receptor affinity. 5-Chloroindole 699929 combined high 5-HT6 receptor affinity with excellent brain penetration and also had good oral bioavailability in both rat and dog.

Graphical abstractThe selective, brain penetrant and orally bioavailable 5-HT6 receptor antagonist 12 (699929) is described.Figure optionsDownload full-size imageDownload as PowerPoint slide