5-Piperazinyl-3-sulfonylindazoles as Potent and Selective 5-Hydroxytryptamine-6 Antagonists

• Published in: Journal of medicinal chemistry 2010-11, Vol.53 (21), p.7639-7646
• Main Authors: Liu, Kevin G, Robichaud, Albert J, Bernotas, Ronald C, Yan, Yinfa, Lo, Jennifer R, Zhang, Mei-Yi, Hughes, Zoe A, Huselton, Christine, Zhang, Guo Ming, Zhang, Jean Y, Kowal, Dianne M, Smith, Deborah L, Schechter, Lee E, Comery, Thomas A
• Format: Article
• Language: English
• Subjects: Acetylcholine - metabolism; Animals; Biological Availability; Brain - metabolism; Glutamic Acid - metabolism; HeLa Cells; Humans; Indazoles - chemical synthesis; Indazoles - pharmacokinetics; Indazoles - pharmacology; Ligands; Nootropic Agents - chemical synthesis; Nootropic Agents - pharmacokinetics; Nootropic Agents - pharmacology; Piperazines - chemical synthesis; Piperazines - pharmacokinetics; Piperazines - pharmacology; Rats; Receptors, Serotonin - metabolism; Serotonin Antagonists - chemical synthesis; Serotonin Antagonists - pharmacokinetics; Serotonin Antagonists - pharmacology; Structure-Activity Relationship; Sulfones - chemical synthesis; Sulfones - pharmacokinetics; Sulfones - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm1007825

As part of our efforts to develop agents for CNS diseases, we have been focused on the 5-HT6 receptor in order to identify potent and selective ligands for cognitive enhancement. Herein we report the identification of a novel series of 5-piperazinyl-3-sulfonylindazoles as potent and selective 5-HT6 antagonists. The synthesis, SAR, and pharmacokinetic and pharmacological activities of some of the compounds including 3-(naphthalen-1-ylsulfonyl)-5-(piperazin-1-yl)-1H-indazole (WAY-255315 or SAM-315) will be described.