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Pharmacokinetic characterization of 2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone, a novel 11β-hydroxysteroid dehydrogenase type 1 inhibitor in rats

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Abstract

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.

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Authors and Affiliations

  1. Drug Discovery Platform Technology Group, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon, 305-600, Republic of Korea

    Zhi Zheng, Hyewon Seo, Ki Young Kim, Myung Ae Bae & Jin Sook Song

  2. Medicinal Chemistry Research Center, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon, 305-600, Republic of Korea

    Hyun Jung Kwak & Jin Hee Ahn

  3. Department of Toxicology, School of Public Health, Xinxiang Medical University, Henan, China

    Zhi Zheng

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  1. Zhi Zheng
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  2. Hyewon Seo
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  3. Hyun Jung Kwak
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  4. Ki Young Kim
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  5. Jin Hee Ahn
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  6. Myung Ae Bae
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  7. Jin Sook Song
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Correspondence to Jin Sook Song.

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Zheng, Z., Seo, H., Kwak, H.J. et al. Pharmacokinetic characterization of 2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone, a novel 11β-hydroxysteroid dehydrogenase type 1 inhibitor in rats. Arch. Pharm. Res. 39, 492–498 (2016). https://doi.org/10.1007/s12272-015-0702-8

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  • DOI: https://doi.org/10.1007/s12272-015-0702-8

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