Phenylcyclobutyl triazoles as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type I

3-(Phenylcyclobutyl)-1,2,4-triazoles were identified as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). These were active both in vitro and in an in vivo mouse pharmacodynamic (PD) model. Fluorine substitution of the cyclobutane ring improved the pharmacokinetic pro...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2008-06, Vol.18 (11), p.3412-3416
Hauptverfasser:	Zhu, Yuping, Olson, Steven H, Graham, Donald, Patel, Gool, Hermanowski-Vosatka, Anne, Mundt, Steven, Shah, Kashmira, Springer, Marty, Thieringer, Rolf, Wright, Samuel, Xiao, Jianying, Zokian, Hratch, Dragovic, Jasminka, Balkovec, James M
Format:	Artikel
Sprache:	eng
Schlagworte:	11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors Administration, Oral Animals Combinatorial Chemistry Techniques Cortisone - analysis Cortisone - blood Disease Models, Animal Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - pharmacology Humans Hydrocortisone - analysis Hydrocortisone - blood Mice Models, Molecular Molecular Structure Structure-Activity Relationship Triazoles - chemical synthesis Triazoles - pharmacokinetics Triazoles - pharmacology
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Zusammenfassung:	3-(Phenylcyclobutyl)-1,2,4-triazoles were identified as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). These were active both in vitro and in an in vivo mouse pharmacodynamic (PD) model. Fluorine substitution of the cyclobutane ring improved the pharmacokinetic profile significantly. The synthesis and structure-activity relationships are presented.
ISSN:	1464-3405
DOI:	10.1016/j.bmcl.2008.04.014