Novel 1-(arylsulfonyl)-3-(piperidinylmethyl)-1H-indoles as potent and selective 5-HT6 antagonists

MEDI 41

Ping Zhou, zhoup@wyeth.com1, Yanfang Li, liy1@wyeth.com1, Boyd L. Harrison, harrisb3@wyeth.com1, Guo Ming Zhang2, Deborah Smith2, Michael G. Kelly1, Lee Schechter2, and Albert J Robichaud1. (1) Chemical and Screening Sciences, Wyeth Research, Princeton, NJ 08543, (2) Department of Neuroscience, Wyeth Research, Princeton, Princeton, NJ 08543
The 5-HT6 serotonin receptor subtype is one of the seven major types of serotonin receptors (5-HT1-5-HT7). This receptor is a member of the seven-transmembrane-spanning G-protein-coupled receptor family that is positively coupled to adenylate cyclase. The potential role of selective 5-HT6 receptor ligands in the treatment of various central nervous system disorders such as depression, anxiety, cognition, and feeding disorders has stimulated a surge of interest in this area. A novel class of 1-(arylsulfonyl)-3-(piperidinylmethyl)-1H-indoles was designed and prepared as potent and selective 5-HT6 ligands. Among these, compound 1 showed excellent affinity (Ki = 1 nM) towards the 5-HT6 receptor, and excellent selectivity over 5-HT7 receptor. In addition, compound 1 is a full antagonist in a 5-HT6 functional assay with superior potency (IC50 = 1.3 nM)

 

Poster Session
7:00 PM-9:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

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