Tricyclic azepine derivatives as selective brain penetrant 5-HT6 receptor antagonists

Starting from a benzazepine sulfonamide 5-HT(6) receptor antagonist lead with limited brain penetration, application of a strategy of conformational constraint and reduction of hydrogen bond donor count led to a novel series of tricyclic derivatives with high 5-HT(6) receptor affinity and excellent...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2008-10, Vol.18 (20), p.5698-5700
Hauptverfasser:	TRANI, Giancarlo, BADDELEY, Stuart M, QUINN, Leann P, RAY, Alison M, RIVERS, Dean A, STEAN, Tania O, STEMP, Geoffrey, TRAIL, Brenda K, WITTY, David R, BRIGGS, Michael A, CHUANG, Tsu T, DEEKS, Nigel J, JOHNSON, Christopher N, KHAZRAGI, Abir A, MEAD, Tania L, MEDHURST, Andrew D, MILNER, Peter H
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Antidepressive Agents, Tricyclic - chemical synthesis Antidepressive Agents, Tricyclic - pharmacology Biological and medical sciences Blood-Brain Barrier - drug effects Brain - drug effects Chemistry, Pharmaceutical - methods Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme System - chemistry Humans Hydrogen Bonding Medical sciences Microsomes - drug effects Models, Chemical Molecular Conformation Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Protein Isoforms Rats Receptors, Serotonin - chemistry Serotonin Antagonists - chemical synthesis Serotonin Antagonists - pharmacology Serotoninergic system
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Zusammenfassung:	Starting from a benzazepine sulfonamide 5-HT(6) receptor antagonist lead with limited brain penetration, application of a strategy of conformational constraint and reduction of hydrogen bond donor count led to a novel series of tricyclic derivatives with high 5-HT(6) receptor affinity and excellent brain:blood ratios.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2008.08.010