Discovery of novel SSRIs for a combination-treatment with pimavanserin

A growing body of evidence indicates that inadequate symptom-relief from medical treatment with SSRIs may be enhanced by concomitant blockade of 5-HT_2A. In a discovery program directed towards finding novel SSRIs suitable for combining with the 5-HT_2A inverse agonist pimavanserin, we used a published in silico generated template as the starting point. Through a stepwise optimization of the template, we discovered that by first exchanging a benzyl substituent for a pyridyl-methyl substituent and then by introducing either a 5- or 6-membered aromatic heterocycle on the core benzene-ring, new compounds with improved metabolic stability and enhanced SERT-potency were obtained. The novel SSRIs had desirable ADME properties, decreased CYP-inhibition and comparable in vivo activity to commonly prescribed SSRIs. One compound (21d) selected for further characterization displayed high selectivity across 90 targets, and synergistic actions with pimavanserin in behavioral tests of anxiety and in microdialysis assessments of neurotransmitter release.