Aleglitazar, a new, potent, and balanced dual PPARalpha/gamma agonist for the treatment of type II diabetes.
Design, synthesis, and SAR of novel alpha-alkoxy-beta-arylpropionic acids as potent and balanced PPARalphagamma coagonists are described. One representative thereof, Aleglitazar ((S)-2Aa), was chosen for clinical development. Its X-ray structure in complex with both receptors as well as its high efficacy in animal models of T2D and dyslipidemia are also presented.
Bénardeau
Agnes
A
F. Hoffmann-La Roche Ltd, Pharma Research, CH-4070 Basel, Switzerland.
Benz
Jörg
J
Binggeli
Alfred
A
Blum
Denise
D
Boehringer
Markus
M
Grether
Uwe
U
Hilpert
Hans
H
Kuhn
Bernd
B
Märki
Hans Peter
HP
Meyer
Markus
M
Püntener
Kurt
K
Raab
Susanne
S
Ruf
Armin
A
Schlatter
Daniel
D
Mohr
Peter
P
D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D015195:Drug Design; D050171:Dyslipidemias / Q000188:drug therapy; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008956:Models, Chemical; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology*
D008024:Ligands; D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D018160:Receptors, Cytoplasmic and Nuclear; D013876:Thiophenes; C542437:aleglitazar