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.


OBJECTIVE
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.


CONCLUSIONS
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.
Wu
Guan Zhong
GZ
Department of Pharmacology, China Pharmaceutical University, Nanjing, PR China. zhonghuw@sohu.com
Hong
Gang
G
Zhang
Wen Ping
WP
Zhang
Hui Bing
HB
D000818:Animals; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy; D004041:Dietary Fats / Q000494:pharmacology; D005941:Glucokinase / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006003:Glycogen / Q000096:biosynthesis; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
C547418:1-(4-(2-(4-bromobenzenesulfonamino) ethyl) phenylsulfonyl)-3-(trans-4-methylcyclohexyl)urea; D004041:Dietary Fats; D007004:Hypoglycemic Agents; D007202:Indicators and Reagents; D007328:Insulin; D013438:Sulfhydryl Compounds; D014508:Urea; D006003:Glycogen; D005941:Glucokinase; D005947:Glucose