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P4‐326: Behavioural symptoms in Alzheimer's disease increase resource utilisation
Author(s) -
Orgogozo Jean-Marc
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.2396
Subject(s) - irritability , apathy , anxiety , aggression , psychiatry , medicine , depression (economics) , psychology , clinical psychology , cognition , economics , macroeconomics
related to aging, Alzheimer’s disease (AD) and Schizophrenia. Thus serotonergic system became a potential target for the treatment of memory dysfunction. Methods: Our effective lead generation and optimization methods have resulted in a potent 5-HT6 receptor antagonist SUVN-502 with Ki of 1.71 nM. SUVN-502 exhibited antagonist like inhibition with EC50 of 0.103 M 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). Results: 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. Conclusions: 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.