Substituted phenyl triazoles as selective inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1

Wanying Sun; Milana Maletic; Steven S Mundt; Kashmira Shah; Hratch Zokian; Kathy Lyons; Sherman T Waddell; James Balkovec

doi:10.1016/j.bmcl.2011.01.125

Substituted phenyl triazoles as selective inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1

Bioorg Med Chem Lett. 2011 Apr 1;21(7):2141-5. doi: 10.1016/j.bmcl.2011.01.125. Epub 2011 Feb 2.

Authors

Wanying Sun¹, Milana Maletic, Steven S Mundt, Kashmira Shah, Hratch Zokian, Kathy Lyons, Sherman T Waddell, James Balkovec

Affiliation

¹ Department of Medicinal Chemistry, Merck & Co, Inc, PO Box 2000, Rahway, NJ 07065, USA. [email protected]

PMID: 21334894
DOI: 10.1016/j.bmcl.2011.01.125

Abstract

3-(Phenylcyclobutyl)-1,2,4-triazoles were identified as inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 (HSD1). They were shown to be active in the mouse in vivo pharmacodynamic model (PD) for HSD1 but exhibited a potent off-target activation of the Pregnane X Receptor (PXR). SAR studies and synthesis of analogs that led to the discovery of a selective HSD1 inhibitor are described in detail.

MeSH terms

11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
Models, Molecular
Triazoles / chemistry*
Triazoles / pharmacology*

Substances

Enzyme Inhibitors
Triazoles
11-beta-Hydroxysteroid Dehydrogenase Type 1