Epiminocyclohepta[b]indole analogs as 5-HT6 antagonists

The synthesis and SAR of epiminocyclohepta[b]indole analogs as 5-HT6 antagonists are described. A new series of epiminocyclohepta[b]indoles with potent 5-HT6 antagonist activity were discovered and optimized using in vitro protocols. One compound from this series was progressed to advanced pharmacok...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2012-02, Vol.22 (4), p.1494-1498
Hauptverfasser:	Henderson, Alan J., Guzzo, Peter R., Ghosh, Animesh, Kaur, Jagjit, Koo, Jia-Man, Nacro, Kassoum, Panduga, Shailaja, Pathak, Rashmi, Shimpukade, Bharat, Tan, Valentina, Xiang, Kai, Wierschke, Jonathan D., Isherwood, Matthew L.
Format:	Artikel
Sprache:	eng
Schlagworte:	5-HT6 Administration, Oral Animals antagonists autoradiography Biological and medical sciences Caco-2 Cells chemistry Cognition Humans indoles Indoles - administration & dosage Indoles - chemistry Indoles - pharmacokinetics Indoles - pharmacology Medical sciences Molecular Structure pharmacokinetics Pharmacology. Drug treatments Protein Binding - drug effects Purinergic P1 Receptor Antagonists Rats Rats, Sprague-Dawley Receptors, Serotonin - chemistry Receptors, Serotonin - metabolism SAR Serotonin Serotonin Antagonists - administration & dosage Serotonin Antagonists - pharmacokinetics Serotonin Antagonists - pharmacology Structure-Activity Relationship Weight loss
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Zusammenfassung:	The synthesis and SAR of epiminocyclohepta[b]indole analogs as 5-HT6 antagonists are described. A new series of epiminocyclohepta[b]indoles with potent 5-HT6 antagonist activity were discovered and optimized using in vitro protocols. One compound from this series was progressed to advanced pharmacokinetic (PK) studies followed by 5-HT6 receptor occupancy studies. The compound was found to have excellent oral absorption, a highly favorable PK profile and demonstrated pharmacodynamic interaction with the 5-HT6 receptor as shown by ex vivo autoradiography.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2012.01.022