Pharmacological characteristics of a novel nonthiazolidinedione insulin sensitizer, FK614.
We evaluated antidiabetic effects of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3 H-benzimidazole-5-carboxamide (FK614), a benzimidazole derivative without a thiazolidinedione structure, which was obtained using C57BL/KsJ-db/db mice (db/db mice). In db/db mice, the potency of FK614 for hypoglycemic effect was comparable to that of rosiglitazone and approximately 15-fold greater than that of pioglitazone. FK614 also showed a potent attenuating effect on hypertriglyceridemia in db/db mice, as well as rosiglitazone and pioglitazone. In C57BL/6J-ob/ob mice (ob/ob mice), ED(50) values of FK614 and pioglitazone for hypoinsulinemic effect were 1.3 and 11.8 mg/kg, respectively. FK614 also improved the impaired glucose tolerance in ob/ob mice. In normal rats, FK614 did not influence plasma glucose and insulin levels but significantly decreased both plasma triglyceride and nonesterified fatty acid levels. FK614 was found to activate peroxisome proliferator-activated receptor (PPAR)gamma-mediated transcriptional activity in the reporter gene assay as well as thiazolidinedione derivatives, although its maximum effect was less than that of thiazolidinedione derivatives. In rat toxicity studies, hemodilution effects for FK614 were less than that for rosiglitazone. Overall, these studies suggest that FK614 improves insulin resistance in such animal models through activation of PPARgamma-mediated transcriptional activity and that it would be a new therapeutic candidate with potential for the treatment of type 2 diabetic patients.
Minoura
Hideaki
H
Research Division, Fujisawa Pharmaceutical Co., Ltd., 2-1-6, Kashima, Yodogawa, Osaka 532-8514, Japan. hideaki_minoura@po.fujisawa.co.jp
Takeshita
Shigeru
S
Ita
Makoto
M
Hirosumi
Jiro
J
Mabuchi
Miyuki
M
Kawamura
Ikuo
I
Nakajima
Satoko
S
Nakayama
Osamu
O
Kayakiri
Hiroshi
H
Oku
Teruo
T
Ohkubo-Suzuki
Akiko
A
Fukagawa
Masao
M
Kojo
Hitoshi
H
Hanioka
Kenichi
K
Yamasaki
Noritsugu
N
Imoto
Takafumi
T
Kobayashi
Yoshinori
Y
Mutoh
Seitaro
S
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology* / Q000633:toxicity; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000633:toxicity; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000378:metabolism; D000077205:Pioglitazone; D010957:Plasmids / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000627:therapeutic use; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
C496142:3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3 H-benzimidazole-5-carboxamide; D001562:Benzimidazoles; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D008055:Lipids; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077205:Pioglitazone