title: 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.
abstract: 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 × 10⁻⁶cm/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 T(max), demonstrating its limited absorption into the systemic circulation.
authors.affiliation: Drug Discovery Platform Technology Research Group, Division of Bio-organic Science, Korea Research Institute of Chemical Technology , Daejeon , Republic of Korea and.
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Kwak
authors.forename: So Hee
authors.initials: SH
authors.lastname: Im
authors.forename: Hyewon
authors.initials: H
authors.lastname: Seo
authors.forename: Woon-Ki
authors.initials: WK
authors.lastname: Cho
authors.forename: Ye-Lim
authors.initials: YL
authors.lastname: Lee
authors.forename: Jaechun
authors.initials: J
authors.lastname: Woo
authors.forename: Sunjoo
authors.initials: S
authors.lastname: Ahn
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Ahn
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Kwak
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Ahn
authors.forename: Myung Ae
authors.initials: MA
authors.lastname: Bae
authors.forename: Jin Sook
authors.initials: JS
authors.lastname: Song
mesh_terms: D000085:Acetates / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism / Q000493:pharmacokinetics*; D001798:Blood Proteins / Q000378:metabolism; D018938:Caco-2 Cells / Q000187:drug effects; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D008658:Inactivation, Metabolic; D007408:Intestinal Absorption; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C000591715:2-(4-(4-(5-(2-phenyl-5-(trifluoromethyl)oxazole-4-carboxamido)-1H-benzo(d)imidazol-2-yl)phenyl)cyclohexyl)acetic acid; D000085:Acetates; D001562:Benzimidazoles; D001798:Blood Proteins; D004791:Enzyme Inhibitors; C494881:DGAT1 protein, human; D051048:Diacylglycerol O-Acyltransferase