title: Discovery of novel dual functional agent as PPARgamma agonist and 11beta-HSD1 inhibitor for the treatment of diabetes.
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.
authors: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors: Yang-liang
authors: YL
authors: Ye
authors: Zhou
authors: Z
authors: Zhou
authors: Han-jun
authors: HJ
authors: Zou
authors: Yu
authors: Y
authors: Shen
authors: Ti-Fei
authors: TF
authors: Xu
authors: Jing
authors: J
authors: Tang
authors: Hua-zhong
authors: HZ
authors: Yin
authors: Min-li
authors: ML
authors: Chen
authors: Ying
authors: Y
authors: Leng
authors: Jian-hua
authors: JH
authors: Shen
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D005223:Fats / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008958:Models, Molecular; D009765:Obesity / Q000139:chemically induced / Q000188:drug therapy*; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D010666:Phenylpropionates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D005223:Fats; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D047495:PPAR gamma; D010666:Phenylpropionates; C470568:alpha-methylhydrocinnamic acid; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1