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.