OT-5226, a Novel Antidiabetic Agent, Potently Ameliorates Glucocorticoid-induced and Genetic Insulin Resistance

• Published in: Japanese Journal of Pharmacology Vol. 71; no. suppl.1; p. 127
• Main Authors: Inoue, Yasuhide, Sato, Keigo, Kanaya, Jun, Kurogi, Yasuhisa, Kohri, Hideaki
• Format: Journal Article
• Language: Japanese; English
• Published: The Japanese Pharmacological Society 1996
• ISSN: 0021-5198; 1347-3506
• DOI: 10.1016/S0021-5198(19)36747-2

OT-5226 (2-[4-[(diethoxyphosphoryl)methyl]phenyl]-7-chloro-3-methyl-4(3H)-quinazolinone) is a newly discovered antidiabetic agent. This compound potently ameliorates dexamethasone-induced insulin resistance and genetic insulin resistance (we used KK-Ay as genetic animal models of NIDDM) . Rats received dexamethasone only (0.5mg/kg/day i p. for 7days), or with OT-5226(Dex for 7days /OT-5226 p.o. 10mg/kg/day for 4days). OT-5226 significantly reduced the elevated fasting glucose, insulin, triglyceride and NEFA levels (30%,36%,100%,67% decrease towards norm0al value respectively) in dexamethasone-treated rats. In KK-Ay as a genetic animal model of NIDDM, OT-5226(0.1% for 4days) also significantly reduced the fed glucose(control; 295± 109 mg/dl,OT-treated; 178±27 mg/dl), insulin(control; 276±183 μU/ml, OT-treated 50±39 μU/ml) and triglyceride(control; 383± 101 mg/dl, OT-treated; 210± 36 mg/dl) levels. The mechanisms of action of OT-5226 which are presently clear are first, the inhibition of hepatic gluconeogenesis, and second the elevation of glucose utilization in skeletal muscle. In an experiment of gluconeogenesis in perfused rat liver (L-alanine was used as a substrate of gluconeogenesis), OT-5226 decreased gluconeogenesis in a dose dependent manner(10～30μM). In an experiment of glucose utilization in skeletal muscle using the euglycemic clamp technique, OT-5226(100mg/kg) had no influence on glucose utilization in normal rats. However, when the lower glucose utilization was caused by dexamethasone, OT-5226(100mg/kg) improved it [GIR(mg/ kg/min)：normal;.19.0 ± 0.8, Dex-treated; 3.2±0.3, Dex/ OT-treated; 10.5± 1.3]. These results indicate that OT-5226 may be a useful pharmacological agent for the treatment of NIDDM.