Glucose concentration-dependent potentiation of insulin secretion by a new chemical entity, KCP256.
The insulinotropic activity of KCP256 [(R)-8-benzyl-2-cyclopentyl-7, 8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride] was examined using MIN6 cells (a pancreatic beta-cell line) and pancreatic islets isolated from rats. Unlike sulfonylurea anti-diabetic drugs, KCP256 dose-dependently (0.1-10 microM) enhanced insulin secretion from MIN6 cells and its insulinotropic effect was exerted only at high concentrations of glucose (8.3-22 mM) but not at low concentrations of glucose (3.3-5.5 mM). Furthermore, the action mechanism of KCP256 was different because, unlike sulfonylurea drugs, KCP256 did not displace the binding of [3H]glibenclamide, and did not inhibit the 86Rb+ efflux nor K(ATP) channel activity. In isolated islets, KCP256 also enhanced insulin secretion in a dose- and a glucose-concentration-dependent manner. Plasma levels of insulin after glucose challenge in KCP256-administrated rats were higher than those in vehicle-administrated animals, indicating that KCP256 can enhance insulin secretion in vivo. Since the insulinotropic activity of KCP256 only occurs at high concentrations of glucose, this novel drug may exhibit a decreased risk of drug-induced hypoglycemia compared with sulfonylurea drugs when treating patients with diabetes.
Mori
Kiyotoshi
K
Drug Discovery Research Laboratories, Pharmaceutical Research Center, Kyowa Hakko Kogyo Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Shizuoka, Japan. kiyotoshi.mori@kyowa.co.jp
Takasaki
Kotaro
K
Katoh
Yoshimitsu
Y
Yano
Hiroshi
H
Ueno
Kimihisa
K
Ichimura
Michiaki
M
Kusaka
Hideaki
H
Nomoto
Yuji
Y
Higo
Katsuya
K
Nakanishi
Satoshi
S
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005947:Glucose / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011687:Purines / Q000494:pharmacology*; D011688:Purinones / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
C508441:(R)-8-benzyl-2-cyclopentyl-7, 8-dihydro-4-propyl-1H-imidazo(2,1-i)purin-5(4H)-one hydrochloride; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007093:Imidazoles; D007328:Insulin; D011687:Purines; D011688:Purinones; D005947:Glucose