Sulfonyliminoimidazolidines, a new class of oral hypoglycemic agents. 4. Toxicity and general pharmacology of 1-[p-[2-(crotonylamino)-ethyl]-phenylsulfonyl]-3-cyclohexy l-2-imino- imidazolidine (CGP 11 112).
Results of a first segment of toxicity tests and general pharmacological investigations with 1-[p-[2-(crotonylamino)-ethyl]-phenylsulfonyl]-3-cyclohexyl- 2- iminoimidazolidine (CGP 11 112), a potent new oral hypoglycemic agent, are reported. The acute LD50 in rats was 600 mg/kg p.o. and 25 mg/kg i.v. In a range finding study doses of 60 mg/kg p.o. and 10 mg/kg i.p., administered daily for 10 days, were tolerated without symptoms in rats, and 30 mg/kg p.o. produced no unequivocal toxic effects in dogs. Slight and transient increases of blood pressure were observed in anaesthetized cats at doses of 0.3 mg/kg i.v. and above. 3 mg/kg i.v. (1/10 LD) caused a transient blood pressure decrease. Heart rate, tidal volume and blood pressure effects of epinephrine (adrenaline), norepinephrine (noradrenaline) and acetylcholine were not significantly influenced in a dose range from 0.01 to 1.0 mg/kg i.v. In isolated organ segments, CGP 11 112 produced only unspecific effects at high concentrations. No intrinsic activity, but antagonism against BaCl2-induced contractions were observed in isolated guinea-pig ileum (one third papaverine hydrochloride). Rate and force of contraction of isolated guinea-pig atria were not affected up to 2.4 mumol/l; higher concentrations were cardiodepressant. In rats, CGP 11 112 increased the excretion of urine, sodium and chloride, but not potassium, dose-dependently (range 10-100 mg/kg). Similar effects observed in dogs suggest that the compound may affect fluid and electrolyte balance at high doses. Moderate antiphlogistic activity (ED40 10-40 mg/kg) was observed in the carrageenin-induced rat paw oedema.(ABSTRACT TRUNCATED AT 250 WORDS)
D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents; D002415:Cats; D002490:Central Nervous System / Q000187:drug effects; D004285:Dogs; D004573:Electrolytes / Q000652:urine; D005260:Female; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000633:toxicity; D007093:Imidazoles / Q000494:pharmacology* / Q000633:toxicity; D048289:Imidazolidines; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D051381:Rats; D013045:Species Specificity
D000893:Anti-Inflammatory Agents; D004573:Electrolytes; D007004:Hypoglycemic Agents; D007093:Imidazoles; D048289:Imidazolidines; C038573:1-((4-(2-(crotonylamino)ethyl)phenyl)sulfonyl)-3-cyclohexyl-2-iminoimidazolidine