SUMMARY 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 pre- requisites for the maintenance of this activity were investigated. Of most interest was compound 3–15 ((N-[(4-methylphenyl- sulphonyl]-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. Key words: glibenclamide, metformin, non-insulin-dependent diabetes mellitus, sulphonylthioureas, Zucker rats. INTRODUCTION The aetiology of overt non-insulin-dependent diabetes mellitus (NIDDM) is complex, but is clearly characterized by chronic hyper- glycaemia. It is associated with multiple defects, namely impaired insulin secretion from pancreatic -cells as well as insulin resistance in peripheral tissues. Non-insulin-dependent diabetes mellitus is a progressive disease, such that the spiralling cycle of hyper- insulinaemia and insulin resistance ultimately leads to the hypoinsulinaemia and ultimately macrovascular and microvascular complications if not adequately controlled. There have been several main approaches to the pharmacological control of NIDDM. First, sulphonylureas, such as glibenclamide, improve insulin secretion by blocking pancreatic KATP channels. Metformin and the thiazolidinediones, in contrast, both elicit their action by improving insulin sensitivity. Metformin specifically decreases hepatic glucose production and promotes insulin- mediated glucose uptake in muscle. 1 The main mechanism of action of thiazolidinediones is in adipose tissue, where they have been shown to have high affinity for the peroxisome proliferator-activated  receptor (PPAR). This results in adipocyte differentiation and favours insulin sensitivity. 2–4 The present pharmacological approaches to NIDDM are far from ideal. The most common and disturbing side effect of many sulphonylureas is hypoglycaemia, because a deficiency in glucose concentration of less than 2 mmol/L increases the risk of neurological damage. 5 Despite the popular use of metformin, it has been associ- ated with serious side effects, such as lactic acidosis as well as weight loss and the milder gastrointestinal disturbances. 6–8 Although lactic acidosis is rare among patients taking metformin, mortality risks for metformin-associated lactic acidosis (MALA) are comparable with glibenclamide-induced hypoglycaemia. 7 In addition, as a result of the action of thiazolidinediones at the adipose tissue, they ultimately promote fat accumulation in the adipose tissue and are not recom- mended in obese patients. Furthermore, an increased risk of liver failure has been seen in some patients administered the thiazo- lidinedione troglitazone 9 and this has resulted in its recent removal from the world market. Ultimately, there often is inadequate metabolic control over time with monotherapy because the present pharmacological agents either aim to treat impaired insulin secre- tion from the pancreas (sulphonylureas) or improve insulin sensi- tivity in peripheral tissues (metformin and thiazolidinediones), but not both. Combination therapy often occurs because there is no evidence of significant drug interactions with such treatment; 10 however, there are greater demands in terms of complexity of dosing and potential for errors that may result in patient non- compliance. EFFECT OF A SERIES OF NOVEL SULPHONYLTHIOUREAS ON GLUCOSE TOLERANCE IN THE OBESE fa/fa ZUCKER RAT Nicole S Farrar, Noel J Chambers, Anthony R Carlsson, Gareth Denyer and Graham AR Johnston Department of Pharmacology, The University of Sydney, Sydney, New South Wales, Australia Correspondence: Nicole Farrar, Room 297, Department of Pharmacology, The University of Sydney, Sydney, NSW 2006, Australia. Email: nikki@pharmacol.usyd.edu.au Received 30 May 2000; revision 20 November 2000; accepted 28 November 2000. Clinical and Experimental Pharmacology and Physiology (2001) 28, 386–391