Novel Tricyclic-α-alkyloxyphenylpropionic Acids:  Dual PPARα/γ Agonists with Hypolipidemic and Antidiabetic Activity

Synthesis and structure−activity relationships of tricyclic α-ethoxy-phenylpropionic acid derivatives guided by in vitro PPARα and PPARγ transactivation data and computer modeling led to the identification of the novel carbazole analogue, 3q, with dual PPARα (EC₅₀ = 0.36 μM) and PPARγ (EC₅₀ = 0.17 μM) activity in vitro. Ten days treatment of db/db mice with 3q improved the insulin sensitivity, as measured by OGTT, better than that seen with both pioglitazone and rosiglitazone treatment, suggesting in vivo PPARγ activity. Likewise, 3q lowered plasma triglycerides and cholesterol in high cholesterol fed rats after 4 days treatment, indicating in vivo PPARα activity. Investigations of the pharmacokinetics of selected compounds suggested that extended drug exposure improved the in vivo activity of in vitro active compounds.