Thiazolidinediones improve insulin sensitivity in type 2 diabetes mellitus by acting as peroxisome proliferator-associated receptor gamma (PPARgamma) agonists, and decrease circulating androgen concentrations in polycystic ovary syndrome by unknown mechanisms. Some thiazolidinediones directly inhibit the steroidogenic enzymes P450c17 and 3beta-hydroxysteroid dehydrogenase type II (3betaHSDII) by distinct mechanisms. We synthesized five novel thiazolidinediones, CLX-M1 to -M5 by linking a 2,4-thiazolidinedione moiety to a substituted alpha-phenyl cinnamic acid previously shown to have glucose-lowering effects. Using yeast microsomes expressing human P450c17 and 3betaHSDII we found that cinnamic acid methyl esters with a double bond in the thiazolidinedione core structure (M3, M5) were stronger inhibitors of P450c17 than methyl esters with the conventional core (M1, M4). These four compounds inhibited 3betaHSDII equally well, while the free cinnamic acid analog (M2) did not inhibit either enzyme. Thus, the inhibition of P450c17 and 3betaHSDII by these novel thiazolidinediones reveals structure-activity relationships independent of PPARgamma transactivation. PPARgamma transactivation was moderate (M1), weak (M2, M3) or even absent (M4, M5). While the PPARgamma agonist activity of M1 was only 3% of that of rosiglitazone, both increased glucose uptake by 3T3-L1 adipocytes and reduced serum glucose levels in ob/ob and db/db mice to a similar extent. The similar glucose-lowering effects of M1 and rosiglitazone, despite their vast differences in PPARgamma agonist activity, suggests these two actions may occur by separate mechanisms.

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