Discovery of 4-heteroarylbicyclo[2.2.2]octyltriazoles as potent and selective inhibitors of 11beta-HSD1: novel therapeutic agents for the treatment of metabolic syndrome.
Replacement of the pentyl chain on our original bicyclo[2.2.2]octyltriazole leads 1 and 2 has led to the discovery that heteroaryl substituted bicyclo[2.2.2]octyltriazoles are potent and selective 11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1) inhibitors with excellent pharmacokinetic profiles.
Gu
Xin
X
Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA. xin_gu@merck.com
Dragovic
Jasminka
J
Koo
Gloria C
GC
Koprak
Sam L
SL
LeGrand
Cheryl
C
Mundt
Steven S
SS
Shah
Kashmira
K
Springer
Marty S
MS
Tan
Eugene Y
EY
Thieringer
Rolf
R
Hermanowski-Vosatka
Anne
A
Zokian
Hratch J
HJ
Balkovec
James M
JM
Waddell
Sherman T
ST
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D024821:Metabolic Syndrome / Q000188:drug therapy*; D051379:Mice; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*
D004791:Enzyme Inhibitors; D014230:Triazoles; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1