11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is associated with metabolic syndromes such as type 2 diabetes mellitus and obesity. A new 11β-HSD1 inhibitor known as 2-(3-benzoyl)-4-hydroxy-1, 1-dioxo-2H-1, 2-benzothiazine-2-yl-1-phenylethanone (KR-66344) is being developed as a therapeutic agent for these metabolic diseases. The purpose of this study was to characterize the pharmacokinetics of KR-66344 to support further preclinical development. KR-66344 showed high liver microsomal stability with T1/2 values >3 h and high permeability with apparent permeability coefficients of 15.2-24.2 × 10(-6) cm/s in Caco-2 cell monolayers. KR-66344 was also strongly bound to plasma proteins (>98%). After intravenous dosing, KR-66344 exhibited low systemic clearance (0.27-0.37 L/h/kg) and a low to moderate volume of distribution at steady state (0.79-0.8 L/kg). The bioavailability and terminal half-lives of KR-66344 following oral administration were 25% and 1.7-3.3 h, respectively. In addition, KR-66344 showed dose-independent pharmacokinetics at 0.5-10 mg/kg in intravenous and oral pharmacokinetic studies.
Keywords: 11β-hydroxysteroid dehydrogenase type 1; Caco-2 cell permeability; Metabolic stability; Pharmacokinetics; Plasma protein binding.