S15261, A NEW COMPOUND FOR THE TREATMENT OF THE INSULIN-RESISTANCE SYNDROME

A new oral agent, S15261 (the L-isomer of 3-[2- [2- [4- [2- [alpha-flu orenyl acetyl amino ethyl] benzoyloxy] ethyl amino] 1-methoxy ethyl] t rifluoromethylbenzene), has been developed for the treatment of the so -called ''insulin resistance syndrome''. In obese, insulin-resistant a geing Sprague-Dawley rats, chronic treatment with S15261 (0.5-2.5 mg k g(-1) day(-1) twice per day, for 14 days) resulted in dose-dependent d ecreases in plasma insulin (43%), and triglyceride levels (36%), and i n an increase of the glucose disposal rate during an intravenous gluco se tolerance test (IVGTT) (48.5%). An increase in peripheral insulin s ensitivity produced by S15261 was revealed by the glucose clamp techni que. Thus, the glucose infusion rate was increased by 20% whilst stead y-state insulin levels decreased by 15%. At the higher doses S15261 le d to a decrease in body weight (3%), plasma glucose (13%) and blood pr essure (8 mmHg) in mildly hypertensive animals. At the doses used to a chieve these results, the compound has no hypoglycaemic activity in no rmoglycaemic animals. Acute administration of S15261 directly into the portal vein provoked a marked increase in glucose disappearance rate during an intravenous glucose tolerance test (60%) and also in the pan creatic response to the glucose challenge. Thus, acute administration of the compound has a direct eff ect on glucose metabolism. These data suggest that S15261 could be a useful agent for the treatment of the insulin resistance syndrome.