P4-325: A potent selective brain penetrant and orally active 5-HT 6 receptor antagonist SUVN-502 for the symptomatic treatment of Alzheimer's disease

Abstract

5-HT6 receptors exclusive distribution in brain regions such as cerebral cortex, nucleous accumbens, caudate-putamen and hipocampus with high densities and thalamus, and substantia nigra with low densities, which are associated with learning and memory. Compromised serotonergic function may have been an important contribution to cognitive decline related to aging, Alzheimer's disease (AD) and Schizophrenia. Thus serotonergic system became a potential target for the treatment of memory dysfunction. Our effective lead generation and optimization methods have resulted in a potent 5-HT6receptor antagonist SUVN-502 with Ki of 1.71 nM. SUVN-502 exhibited antagonist like inhibition with EC50 of 0.103 μM when tested for functional activity. SUVN-502 has more than 100 fold selectivity against the related GPCRs. The effective optimization of its critical physico-chemical properties has lead to oral bioavailability (31%) and brain penetration index (1.48). SUVN-502 was effective in animal models of cognition. SUVN-502 reversed the age induced memory deficit in Morris water maze and novel object recognition task (NORT). SUVN-502 also reversed the spatial and working memory deficit induced by MK-801 and scopolamine in Morris water maze, NORT and radial arm maze task. The effective dose range of SUVN-502 in the above animal models was between 3 to 10 mg/kg. p.o. Brain microdialysis studies in rats with SUVN-502 showed significant increase in brain acetylcholine and glutamate levels correlating to the in vivo memory models. SUVN-502 has been identified as a candidate for clinical development for the symptomatic treatment of Alzheimer's disease. SUVN-502 has completed all regulatory safety and toxicity studies to enter to human Phase-I clinical trials in 2008.