Effect of 1-[4- [2-(4-bromobenzenesulfonamino) ethyl] phenylsulfonyl]-3-(trans-4-methylcyclohexyl)urea (I4), a new synthetic sulfonylurea compound, on glucose metabolism in vivo and in vitro.

Background: 1-[4-[2-(4-Bromobenzenesulfonamino)ethyl]phenylsulfonyl]-3-(trans-4-methylcyclohexyl)urea (I4, CAS 865483-06-3), a totally synthetic new sulfonylurea compound, incorporating part of the hypoglycemic structure of glimepiride (CAS 93479-97-1) and having anti-TXA2 receptor properties, was designed and synthesized. Its hypoglycemic property had not been reported yet.

Aim: To study the hypoglycemic effects of I4 and its primary mechanisms of action.

Methods: A rat model of type 2 diabetes was established by intraperitoneal injection of small doses of streptozotocin combined with high calorie feeding. Normal fasted mice and type 2 diabetic rats were used to assay the hypoglycemic actions of I4. Blood glucose and immunoreactive insulin concentrations were measured and the effects of I4 on insulin release from rat isolated pancreatic islets were examined. A liver cell line, Hep G2, was used to examine effects on glucose consumption, glycogen synthesis and glucokinase activity.

Results: Oral administration of I4 (1-10 mg/kg) produced a marked, dose-dependent reduction in blood glucose in normal mice and type 2 diabetic rats and improved oral glucose tolerance. Plasma insulin concentrations were increased, and 14 increased insulin release from rat isolated pancreatic islets and from the isolated perfused rat pancreas. I4 (1-100 micromol x L(-1)) also produced an insulin-independent increase in glucose consumption by Hep G2 cells, increased glycogen synthesis and glucokinase activity of these cells. Glimepiride produced similar effects on glucose consumption and glycogen synthesis but did not facilitate glucokinase activity of Hep G2 cells.

Conclusion: I4 markedly improved glucose metabolism in normal animals and type 2 diabetic rats, probably by increasing insulin secretion and stimulating hepatic glucose uptake and glycogen synthesis.