Preclinical pharmacokinetic characterization of 2-(4-(4-(5-(2-phenyl-5-(trifluoromethyl) oxazole-4-carboxamido)-1H-benzo[d]imidazol-2-yl)phenyl) cyclohexyl) acetic acid, a novel DGAT-1 inhibitor

초록

1. A novel diacylglyceride acyltransferase-1 (DGAT-1) inhibitor, 2-(4-(4-(5-(2- phenyl-5-(trifluoromethyl) oxazole-4-carboxamido)-1H-benzo[ d] imidazol-2-yl) phenyl) cyclohexyl) acetic acid (KR-69232), was synthesized for a potential therapeutic use against several metabolic disorders, such as obesity, insulin resistance, and type II diabetes, characterized by excessive triglycerides (TGs) in the blood. 2. The half-lives against phase I metabolism were measured as 75.3 +/- 20.9 min and over 120 min in rat and human liver microsomes, respectively. In Caco-2 cell monolayers, extremely low permeability (<0.13 X 10(-6) cm/s) was seen in the absorptive direction, predicting limited intestinal absorption of KR-69232. This compound was highly bound to rat and human plasma proteins (> 99.8%). 3. With the intravenous administration of KR-69232 in rats (1, 2, and 5 mg/kg), non-linear kinetics were observed at the highest dose, with significantly higher systemic clearance, higher volume of distribution, and lower dose-normalized AUC. Following oral administration, it exhibited low bioavailability (<10%) and was absorbed slowly (T-max, 3.8-5.2 h) over the dose range. We also confirmed that considerable KR-69232 remained in the intestine at Tmax, demonstrating its limited absorption into the systemic circulation.

키워드