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-fluorenyl acetyl amino ethyl] benzoyloxy] ethyl amino] 1-methoxy ethyl] trifluoromethyl-benzene), has been developed for the treatment of the so-called "insulin resistance syndrome". In obese, insulin-resistant ageing Sprague-Dawley rats, chronic treatment with S15261 (0.5-2.5 mg.kg-1.day-1 twice per day, for 14 days) resulted in dose-dependent decreases in plasma insulin (43%), and triglyceride levels (36%), and in an increase of the glucose disposal rate during an intravenous glucose tolerance test (IVGTT) (48.5%). An increase in peripheral insulin sensitivity produced by S15261 was revealed by the glucose clamp technique. Thus, the glucose infusion rate was increased by 20% whilst steady-state insulin levels decreased by 15%. At the higher doses S15261 led to a decrease in body weight (3%), plasma glucose (13%) and blood pressure (8 mm Hg) in mildly hypertensive animals. At the doses used to achieve these results, the compound has no hypoglycaemic activity in normoglycaemic 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 pancreatic response to the glucose challenge. Thus, acute administration of the compound has a direct effect on glucose metabolism. These data suggest that S15261 could be a useful agent for the treatment of the insulin resistance syndrome.
Division of Metabolic Diseases, Institut de Recherches Servier, Suresnes, France.
J
J
Duhault
F
F
Lacour
M
M
Boulanger
O
O
Della-Zuana
D
D
Ravel
M
M
Wierzbicki
J
J
Espinal
D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005449:Fluorenes; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D009765:Obesity / Q000503:physiopathology; D011169:Portal Vein; D051381:Rats; D017207:Rats, Sprague-Dawley; D013577:Syndrome; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D005449:Fluorenes; D005464:Fluorobenzenes; D007328:Insulin; D008112:Liver Glycogen; D014280:Triglycerides; C091921:S 15261; D002784:Cholesterol; D005947:Glucose