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

Yuping Zhu; Steven H Olson; Donald Graham; Gool Patel; Anne Hermanowski-Vosatka; Steven Mundt; Kashmira Shah; Marty Springer; Rolf Thieringer; Samuel Wright; Jianying Xiao; Hratch Zokian; Jasminka Dragovic; James M Balkovec

doi:10.1016/j.bmcl.2008.04.014

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

Bioorg Med Chem Lett. 2008 Jun 1;18(11):3412-6. doi: 10.1016/j.bmcl.2008.04.014. Epub 2008 Apr 10.

Authors

Yuping Zhu¹, Steven H Olson, Donald Graham, Gool Patel, Anne Hermanowski-Vosatka, Steven Mundt, Kashmira Shah, Marty Springer, Rolf Thieringer, Samuel Wright, Jianying Xiao, Hratch Zokian, Jasminka Dragovic, James M Balkovec

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. [email protected]

PMID: 18440812
DOI: 10.1016/j.bmcl.2008.04.014

Abstract

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.

MeSH terms

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*

Substances

Enzyme Inhibitors
Triazoles
11-beta-Hydroxysteroid Dehydrogenase Type 1
Cortisone
Hydrocortisone