Synthesis and SAR of tolylamine 5-HT6 antagonists

The synthesis and SAR of tolylamines with 5-HT6 receptor antagonist activity is presented. The amine, core aromatic, peripheral aromatic, and ether linker moieties of HTS hit 1 were modulated and the effect on potency at 5-HT6 examined. Tolylpiperidine ether 9h was found to possess desirable pharmacokinetic (PK) properties, and was also shown to enhance cognition in the rat novel object recognition paradigm. (c) 2009 Elsevier Ltd. All rights reserved.