Lead Optimization of Thiazolo[5,4-c]piperidines: 3-Cyclobutoxy Linker as a Key Spacer for H3R Inverse Agonists

Lead Optimization of Thiazolo[5,4-c]piperidines: 3-Cyclobutoxy Linker as a Key Spacer for H3R Inverse Agonists

The simpler, the better: H3 histamine receptor (H3R) are of interest as therapeutic targets in cognitive and somnolence disorders. Here, lead optimization of H3R inverse agonists bearing a thiazolo[5,4‐c]piperidine group gave rise to a clinical candidate with a much simpler unprecedented benzamide s...

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Veröffentlicht in:ChemMedChem 2012-12, Vol.7 (12), p.2087-2092
Hauptverfasser: Provins, Laurent, Denonne, Frédéric, Célanire, Sylvain, Christophe, Bernard, Defays, Sabine, Delaunoy, Christel, Delporte, Marie-Laure, Demaude, Thierry, Durieu, Véronique, Gillard, Michel, Hubert, Delphine, Lamberty, Yves, Lorent, Geneviève, Valade, Anne, Vanbellinghen, Alain, Van houtvin, Nathalie
Format: Artikel
Sprache:eng
Schlagworte:
benzamides
cognitive disorders
histamine H3 receptors
structure-activity relationships
thiazoles
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Zusammenfassung:The simpler, the better: H3 histamine receptor (H3R) are of interest as therapeutic targets in cognitive and somnolence disorders. Here, lead optimization of H3R inverse agonists bearing a thiazolo[5,4‐c]piperidine group gave rise to a clinical candidate with a much simpler unprecedented benzamide scaffold, displaying decreased hERG activity while maintaining high brain receptor occupancies.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201200406