ABSTRACT
The synthesis and SAR of tolylamines with 5-HT(6) 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-HT(6) 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.
Subject(s)
Amines/chemistry , Receptors, Serotonin/chemistry , Serotonin Receptor Agonists/chemical synthesis , Animals , Chemistry, Organic/methods , Chemistry, Pharmaceutical/methods , Drug Design , Ethers/chemistry , Inhibitory Concentration 50 , Kinetics , Models, Chemical , Rats , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacology , Structure-Activity RelationshipABSTRACT
The inhibition of the cytosolic isoenzyme BCAT that is expressed specifically in neuronal tissue is likely to be useful for the treatment of neurodegenerative and other neurological disorders where glutamatergic mechanisms are implicated. Compound 2 exhibited an IC50 of 0.8 microM in the hBCATc assays; it is an active and selective inhibitor. Inhibitor 2 also blocked calcium influx into neuronal cells following inhibition of glutamate uptake, and demonstrated neuroprotective efficacy in vivo. SAR, pharmacology, and the crystal structure of hBCATc with inhibitor 2 are described.
