The peroxisome proliferator-activated receptors (PPARs)1
are ligand-activated transcription factors that can be activated by a range of fatty acids and their eicosanoid derivatives, and they function as regulators in the biosynthesis, metabolism, and storage of these compounds (1
). The PPARs bind DNA as heterodimers with the retinoid X receptors to the peroxisome proliferator response elements. Peroxisome proliferator response elements have been identified in the promoter region of a number of genes involved in lipid and carbohydrate metabolism, and the binding site preferences for each PPAR subtype have been shown to differ slightly (9
). The three human isoforms of PPARα, -δ, and -γ (NR1C1, NR1C2, and NR1C3, respectively) show distinct patterns of tissue distribution and ligand preference and control different biological activities. PPARα is a regulator of fatty acid catabolism in the liver (10
), whereas PPARγ plays a key role in adipogenesis (12
). All three isoforms are expressed in macrophages where they are implicated in the control of cholesterol efflux (13
). The use of synthetic PPAR ligands has demonstrated the importance of these receptors in the regulation of lipid and glucose homeostasis and today PPARs are established molecular targets for the treatment of type 2 diabetes and cardiovascular disease. The thiazolidinediones (TZDs), used pharmaceutically as insulin sensitizers, are known activators of PPARγ (15
), whereas hypolipidemic fibrate drugs to some extent exert their effect via PPARα (1
). With the growing understanding of PPAR biology, it has become evident that novel drugs modulating PPAR activity could improve present diabetes treatment and have implications in the treatment of other diseases (19
Crystal structures of PPARα, -δ, and -γ ligand-binding domains (LBDs), in complex with various agonists (5, 21-23), reveal a common binding mode where the ligands form specific hydrogen bonds with residues in, and in the vicinity of, helix 12, also known as activation function 2 (AF2). It is generally believed that agonist binding to NRs induces changes in the dynamics and position of helix 12, which in turn facilitates the recruitment of coactivator proteins resulting in an activation of the transcriptional machinery. The ligand-binding pockets of PPAR LBDs are larger than for other NRs and, as shown for the PPARγ-GW0072 complex (24), allow ligand binding at epitopes distal to helix 12. The GW0072 compound is a poor transactivator and can antagonize TZD-driven adipocyte differentiation (24). Taken together, these observations suggest that the specific hydrogen bonding interactions seen between the agonists and AF2 could act as a necessary molecular switch for transactivation to occur (22, 24).
In opposition to this hypothesis we here describe a new class of PPAR agonists, the 5-substituted 2-benzoylaminobenzoic acids (2-BABAs), which act by binding at the entrance of the ligand pocket and activate the receptor without a direct interaction with helix 12. The 2-BABA compound BVT.13, which selectively activates PPARγ with a similar maximal efficacy as rosiglitazone, was shown to have antidiabetic effects in ob/ob mice.