title: 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.
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.
authors.affiliation: Drug Discovery Platform Technology Group, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon, 305-600, Republic of Korea.|Department of Toxicology, School of Public Health, Xinxiang Medical University, Henan, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Drug Discovery Platform Technology Group, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon, 305-600, Republic of Korea.
authors.forename: Hyewon
authors.initials: H
authors.lastname: Seo
authors.affiliation: Medicinal Chemistry Research Center, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon, 305-600, Republic of Korea.
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Kwak
authors.affiliation: Drug Discovery Platform Technology Group, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon, 305-600, Republic of Korea.
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Kim
authors.affiliation: Medicinal Chemistry Research Center, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon, 305-600, Republic of Korea.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Ahn
authors.affiliation: Drug Discovery Platform Technology Group, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon, 305-600, Republic of Korea.
authors.forename: Myung Ae
authors.initials: MA
authors.lastname: Bae
authors.affiliation: Drug Discovery Platform Technology Group, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon, 305-600, Republic of Korea. jssong@krict.re.kr.
authors.forename: Jin Sook
authors.initials: JS
authors.lastname: Song
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D003499:Cyclic S-Oxides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D015394:Molecular Structure; D011485:Protein Binding; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013843:Thiazines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: C558395:2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone; D001798:Blood Proteins; D003499:Cyclic S-Oxides; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D013843:Thiazines; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1
keywords: 11β-hydroxysteroid dehydrogenase type 1; Caco-2 cell permeability; Metabolic stability; Pharmacokinetics; Plasma protein binding