Effect of a series of novel sulphonylthioureas on glucose tolerance in the obese fa/fa Zucker rat.
1. The recent development of a series of novel KATP channel modulators, namely sulphonylthioureas and sulphonylureas, is thought to make improvements in potency and tissue selectivity compared with current sulphonylureas, such as glibenclamide, which shares a similar structure to the novel compounds. 2. These novel compounds were first examined for their effect on hyperglycaemia and glucose tolerance during an oral glucose tolerance test following 5 days administration in the lean fa/- and obese fa/fa Zucker rat (a model of insulin resistance). Comparisons with present antidiabetic agents, metformin and glibenclamide were performed. 3. Several compounds showed improvements in glucose tolerance compared with control and the primary structural prerequisites for the maintenance of this activity were investigated. Of most interest was compound 3-15 ((N-[(4-methylphenylsulphonyl]-N'-(2-ethoxypyrid-4-yl)thiourea; 0.1 mg/kg per day), which significantly improved glucose tolerance following 5 days administration in the fa/fa Zucker rat. This paralleled the improvement seen in metformin (300 mg/kg per day)-treated fa/fa rats, but compound 3-15 was up to 3000-fold more potent than metformin. 4. Obese fa/fa Zucker rats were then treated with compound 3-15 for 28 days to determine whether glycaemic control could be maintained over the longer term. 5. Compound 3-15 showed a significant improvement in glucose clearance and reduction in insulin concentration following 28 days treatment during an intravenous glucose tolerance test compared with untreated rats, without any change in the rate of weight gain. 6. The novel sulphonylthiourea 3-15 appears to improve glucose clearance during acute and chronic treatment in the fa/fa Zucker rat with no effect on the rate of weight gain. It is thought that compound 3-15 may be eliciting its actions by improving insulin sensitivity, but its effects on insulin secretion are still to be elucidated.
Farrar
N S
NS
Department of Pharmacology, The University of Sydney, Sydney, New South Wales, Australia. nikki@pharmacol.usyd.edu.au
Chambers
N J
NJ
Carlsson
A R
AR
Denyer
G
G
Johnston
G A
GA
D000818:Animals; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D008297:Male; D009765:Obesity / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000494:pharmacology*; D013453:Sulfonylurea Compounds / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology*
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D013450:Sulfones; D013453:Sulfonylurea Compounds; D013890:Thiourea