In Search of Potent 5-HT6 Receptor Inverse Agonists

A series of non‐sulfonamide/non‐sulfone derived potent 5‐HT6 receptor inverse agonists has been disclosed. Representative compound 9 (Ki = 14 nm) displayed selectivity against a set of family members as well as brain permeability 6 h post‐oral administration. In addition, the separated enantiomers o...

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Bibliographic Details
Published in:Chemical biology & drug design 2014-06, Vol.83 (6), p.666-669
Main Authors: Hostetler, Greg, Dunn, Derek, McKenna, Beth Ann, Kopec, Karla, Chatterjee, Sankar
Format: Article
Language:English
Subjects:
5-HT6 receptor
benzazepine
Benzazepines - chemistry
Benzazepines - pharmacology
Biological Assay
CNS disorders
Drug Inverse Agonism
Humans
Molecular Structure
Protein Binding - drug effects
Receptors, Serotonin - chemistry
Sulfonamides - chemistry
Sulfonamides - pharmacology
Sulfones - chemistry
Sulfones - pharmacology
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Summary:A series of non‐sulfonamide/non‐sulfone derived potent 5‐HT6 receptor inverse agonists has been disclosed. Representative compound 9 (Ki = 14 nm) displayed selectivity against a set of family members as well as brain permeability 6 h post‐oral administration. In addition, the separated enantiomers of compound 9 displayed difference in activity indicating the influence of chirality on potency. Based on ‘HTS‐hit’ compound 1a (Ki = 5.73 μm against h5‐HT6), compound 9 (Ki = 14 nm) was developed. Enantiomers of 9 (Ki of 7 nm versus 38 nm) displayed effect of chirality on potency.
ISSN:1747-0277
1747-0285
DOI:10.1111/cbdd.12279