AVE8134, a novel potent PPARα agonist, improves lipid profile and glucose metabolism in dyslipidemic mice and type 2 diabetic rats.
OBJECTIVE
AVE8134 is a structurally novel potent PPARα agonist. The aim of this study is to investigate the efficacy of AVE8134 on lipid profile and glucose metabolism in dyslipidemic mice and type 2 diabetic rats.


METHODS
A cell based PPAR Gal4 transactivation assay was constructed for testing the activities of AVE8134 at 3 different PPAR isoforms in vitro. Transgenic human Apo A1 (hApo A1) mice and insulin-resistant ZDF rats were used to evaluate the effects of AVE8134 in vivo.


RESULTS
AVE8134 was a full PPARα dominated PPAR agonist (the values of EC(50) for human and rodent PPARα receptor were 0.01 and 0.3 μmol/L, respectively). AVE8134 was not active at PPARδ receptor. In female hApo A1 mice, AVE8134 (1-30 mg·kg(-1)·d(-1), po for 12 d) dose-dependently lowered the plasma triglycerides, and increased the serum HDL-cholesterol, hApo A1 and mouse Apo E levels. In female ZDF rats, AVE8134 (3-30 mg·kg(-1)·d(-1) for 2 weeks) improved insulin-sensitivity index. In pre-diabetic male ZDF rats (at the age of 7 weeks), AVE8134 (10 mg·kg(-1)·d(-1) for 8 weeks) produced an anti-diabetic action comparable to rosiglitazone, without the PPARγ mediated adverse effects on body weight and heart weight. In male ZDF rats (at the age of 6 weeks), AVE8134 (20 mg·kg(-1)·d(-1) for 12 weeks) increased mRNA levels of the target genes LPL and PDK4 about 20 fold in the liver, and there was no relevant effect with rosiglitazone.


CONCLUSIONS
AVE8134 improves lipid profile and glucose metabolism in dyslipidemic mice and type 2 diabetic rats.
Diabetes Division, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany.
Hans Ludwig
HL
Schäfer
Wolfgang
W
Linz
Eugen
E
Falk
Maike
M
Glien
Heiner
H
Glombik
Marcus
M
Korn
Wolfgang
W
Wendler
Andreas W
AW
Herling
Hartmut
H
Rütten
D000818:Animals; D001565:Benzoates / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism*; D050171:Dyslipidemias / Q000503:physiopathology*; D005260:Female; D011345:Fenofibrate / Q000627:therapeutic use; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D010080:Oxazoles / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use
C545089:2-methyl-6-(3-(2-phenyloxazol-4-ylmethoxy)propoxymethyl)benzoic acid; D001565:Benzoates; D007004:Hypoglycemic Agents; D008055:Lipids; D010080:Oxazoles; D047493:PPAR alpha; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D005947:Glucose; D011345:Fenofibrate