Design and synthesis of potent 5-HT6 ligands for cognitive impairment

MEDI 256

Hassan Elokdah, elokdah@wyeth.com1, Kevin Liu2, Derek Cole2, Ronald C Bernotas1, Ronald L Magolda2, Lee E. Schechter3, Guo Ming Zhang3, Deborah Smith3, and Albert J Robichaud2. (1) Chemical & Screening Sciences, Wyeth Research, 500 Arcola Rd, Collegeville, PA 19426, (2) Chemical and Screening Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543, (3) Discovery Neuroscience, Wyeth Research, Princeton, NJ 08543
We have earlier reported on the identification of novel ligands for the 5-HT6 receptor within our research group. Potent and selective 5-HT6 receptor ligands are useful in the treatment of CNS disorders such as schizophrenia, depression, and Alzheimer's disease (AD). Our recent efforts focused on the discovery of 5-HT6 receptor antagonists for the treatment of learning and memory deficits in neurodegenerative diseases such as AD. 5-HT6 receptor antagonists are reported to alleviate the cognitive deficits associated with AD through multiple pathways, including the enhancement of the levels of the neurotransmitters acetylcholine and glutamate. Optimization of the binding and functional afinities as well as the pharmaceutical properties of an early series led to the discovery of a series of arylsulfonyl derivatives with high selectivity, excellent binding affinity and potent functional activity. The SAR, in vivo activity as well as changes in neurotransmitter release following oral administration of key derivatives will be presented.
 

Palliative Approaches to the Treatment of Alzheimer's Disease
1:30 PM-4:25 PM, Wednesday, August 22, 2007 BCEC -- 210A, Oral

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007