α-alkyl substituted pirinixic acid derivatives as potent dual agonists of the peroxisome proliferator activated receptor alpha and gamma

Article abstract of DOI:10.1002/ardp.200700209

Peroxisome proliferator-activated receptors (PPAR) are nuclear receptors, playing a pivotal role in energy homeostasis. Activators of the PPARα subtype are in widespread use for the treatment of hyperlipidemia, while activators of the PPARγ subtype are in clinical use for the treatment of type-2 diabetes. Since both of these diseases are frequently associated, the combined treatment with one drug simultaneously activating PPARα and PPARγ seems worthwhile. Starting with pirinixic acid, which is a moderately active dual PPARα/γ agonist, we improved potency at the human PPARα and PPARγ by substituting the a-position with an aliphatic chain. The maximal effect was achieved at a chain length of four and six carbons, respectively, leading to an activity induction by a factor of 36 for PPARα and 18 for PPARγ, respectively.