Abstract
PPARgamma and 11beta-HSD1 are attractive therapeutic targets for type 2 diabetes. However, PPARgamma agonists induce adipogenesis, which causes the side effect of weight gain, whereas 11beta-HSD1 inhibitors prevent adipogenesis and may be beneficial for the treatment of obesity in diabetic patients. For the first time, we designed, synthesized a series of alpha-aryloxy-alpha-methylhydrocinnamic acids as dual functional agents which activate PPARgamma and inhibit 11beta-HSD1 simultaneously. The compound 11e exhibited the most potent inhibitory activity compared to that of the lead compound 2, with PPARgamma (EC(50)=6.76 microM) and 11beta-HSD1 (IC(50)=0.76 microM) in vitro. Molecular modeling study for compound 11e was also presented. Compound 11e showed excellent efficacy for lowering glucose, triglycerides, body fat, in well established mice and rats models of diabetes and obesity and had a favorable ADME profile.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
-
11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
-
Animals
-
Body Weight / drug effects
-
Diabetes Mellitus, Experimental / drug therapy*
-
Fats / metabolism
-
Humans
-
Hypoglycemic Agents / chemistry
-
Hypoglycemic Agents / pharmacokinetics
-
Hypoglycemic Agents / pharmacology
-
Hypoglycemic Agents / therapeutic use*
-
Hypolipidemic Agents / chemistry
-
Hypolipidemic Agents / pharmacokinetics
-
Hypolipidemic Agents / pharmacology
-
Hypolipidemic Agents / therapeutic use*
-
Mice
-
Models, Molecular
-
Obesity / chemically induced
-
Obesity / drug therapy*
-
PPAR gamma / agonists*
-
PPAR gamma / metabolism
-
Phenylpropionates / chemistry
-
Phenylpropionates / pharmacokinetics
-
Phenylpropionates / pharmacology
-
Phenylpropionates / therapeutic use*
-
Rats
-
Rats, Wistar
Substances
-
Fats
-
Hypoglycemic Agents
-
Hypolipidemic Agents
-
PPAR gamma
-
Phenylpropionates
-
alpha-methylhydrocinnamic acid
-
11-beta-Hydroxysteroid Dehydrogenase Type 1