Pharmacological and pharmacokinetic studies of the newly synthesized thiazolidinedione derivative 5-(4-(1-phenyl-1-cyclopropanecarbonylamino)benzyl)-thiazolidine-2 ,4-dio ne.
DN-108 (5-(4-(1-phenyl-1-cyclopropanecarbonylamino)benzyl)thiazolidine-2, 4-dione, CAS 195604-21-8) is a newly synthesized thiazolidinedione derivative. Pharmacological and pharmacokinetic studies of DN-108 were done. In diabetic animal models KKAy and db/db mice, DN-108, orally given at doses of 3-30 mg/kg for 10 consecutive days, improved hyperglycemia, hypertriglyceridemia or hyperinsulinemia from day 1 or day 4 and the effects were almost maintained through the experiment. In KKAy mice, DN-108, orally given at doses of 3-30 mg/kg for 4 consecutive days, potently decreased serum glucose level as compared with troglitazone (CAS 97322-87-7) and the ED25 values of DN-108 and troglitazone were 7 and 283 mg/kg/day, respectively. DN-108 increased 2-deoxyglucose uptake in L6 muscle cell line to the same extent as troglitazone. Moreover, DN-108 inhibited aldose reductase activity in vitro as potently as troglitazone did. Pharmacokinetic parameters, Cmax and AUC of DN-108 after oral administration in rats were higher than those of troglitazone. These results suggest that DN-108 has antidiabetic effect with tissue sensitization for glucose uptake and high absorption after oral administration. It is expected that DN-108 will be a promising oral antidiabetic agent.
Research Laboratories, Torii Pharmaceutical Co., Ltd., Chiba, Japan.
N
N
Ueda
Y
Y
Nomura
Y
Y
Muta
Y
Y
Matsuzaki
M
M
Hayashibe
Y
Y
Ino
S
S
Suzuki
M
M
Kurumi
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002839:Chromans / Q000493:pharmacokinetics / Q000494:pharmacology; D003847:Deoxyglucose / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008870:Microtubules / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D045162:Thiazolidinediones; D014280:Triglycerides / Q000097:blood; D000077288:Troglitazone
D001786:Blood Glucose; D002839:Chromans; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D013844:Thiazoles; D045162:Thiazolidinediones; D014280:Triglycerides; C114240:DN 108; D003847:Deoxyglucose; D000449:Aldehyde Reductase; D000077288:Troglitazone