Introduction
Antagonism of the serotonin subtype 5-HT6 receptor is a promising mechanism for enhancing cognitive function and theurapeutic treatment of various CNS disorders including Alzheimer’s disease, schizophrenia, anxiety, depression, epilepsy and abnormal feeding behaviour. Studies have shown that blockade of the 5-HT6 receptor can increase cortical and hippocampal extracellular acetylcholine and dopamine levels, which is consistent with improved cognitive function (Riemer, C. et al. J. Med. Chem. 2003, 46, 1273). A wide range of 5-HT6 antagonists have been reported as showing positive pro-cognitive effects in various animal models of cognition. Furthermore, a number of 5-HT6 directed compounds have progressed through clinical trials for cognition-related disorders, with the most advanced compounds SB-742457 and LuAE58054 displaying positive improvements in both cognitive and global function in phase II studies for Alzheimer’s disease.
Results and Discussion
A new series of 5-HT6 antagonists was identified through a combination of rational design and consideration of 5-HT6 ligand-receptor pharmacaphore models. An initial hit compound was identified as a low nanomolar 5-HT6 ligand (h5-HT6 Ki = 8.2 nM) based on an epiminocyclohepta[b]indole scaffold. Several compounds were characterized as 5-HT6 antagonists with tractable SAR and favorable in vitro parameters. Advanced compounds were assessed in vivo by employing rat ex vivo receptor occupancy studies which demonstrated significant dose dependent occupancy associated with good brain permeability and potential for efficacy. Studies leading to a related series of potent 5-HT6 antagonists incorporating a non-basic pharmacaphore will also be presented.