Novel rapid- and short-acting hypoglycemic agent, a calcium(2s)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl) propionate (KAD-1229) that acts on the sulfonylurea receptor: comparison of effects between KAD-1229 and gliclazide.
Calcium(2s)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl) propionate dihydrate (KAD-1229) was found to have potent hypoglycemic effects. This study was designed to elucidate its mechanisms by comparing its action with those of the antidiabetic hypoglycemic agents known as sulfonylureas in vivo and in vitro. In fasted beagles, oral administration of 0.1 to 3.0 mg/kg of KAD-1229 induced dose-dependent and significant reductions of plasma glucose levels with 43.4% maximum reduction at 1 hr, and the significant hypoglycemic effects largely disappeared within 2 hr after oral administration; 1.0 to 10 mg/kg of gliclazide also induced dose-dependent and significant reductions of plasma glucose with 44.2% maximum reduction at 3 hr, and the hypoglycemic effects continued for over 7 hr. One and 3.0 mg/kg of KAD-1229 increased plasma insulin levels, with the peak levels at 30 min, whereas 3.0 and 10 mg/kg of gliclazide increased it with the peak levels at 1 to 2 hr after dosing. Similar rapid and short-acting hypoglycemic effects of KAD-1229 were observed in rats. This compound stimulated insulin release from isolated mouse islets at a concentration from 3 x 10(-7) M to 10(-5) M. KAD-1229 stimulated insulin release from hamster's insulin-oma cell line, HIT T15 cells, at a concentration from 10(-8) M to 10(-5) M and inhibited 86Rb+ efflux from these cells with IC50 of 8.4 x 10(-9) M. It also inhibited [3H]glibenclamide binding to microsomes from HIT T15 cells (Ki = 1.3 x 10(-8) M).(ABSTRACT TRUNCATED AT 250 WORDS)
Ohnota
H
H
Creative Products Research Laboratory, Kissei Pharmaceutical Co. Ltd., Japan.
Koizumi
T
T
Tsutsumi
N
N
Kobayashi
M
M
Inoue
S
S
Sato
F
F
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D004285:Dogs; D005907:Gliclazide / Q000494:pharmacology*; D005905:Glyburide / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D054833:Isoindoles; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008861:Microsomes / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects*; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000187:drug effects*; D012413:Rubidium / Q000378:metabolism; D064233:Sulfonylurea Receptors
D018528:ATP-Binding Cassette Transporters; D007004:Hypoglycemic Agents; D007211:Indoles; D007328:Insulin; D054833:Isoindoles; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000255:Adenosine Triphosphate; C087255:mitiglinide; D005907:Gliclazide; D012413:Rubidium; D005905:Glyburide