title: Synthesis and Characterization of a Novel γ-Aminobutyric Acid Type A (GABAA) Receptor Ligand That Combines Outstanding Metabolic Stability, Pharmacokinetics, and Anxiolytic Efficacy.
abstract: 1,4-Benzodiazepines are used in the treatment of anxiety disorders but have limited long-term use due to adverse effects. HZ-166 (2) has been shown to have anxiolytic-like effects with reduced sedative/ataxic liabilities. A 1,3-oxazole KRM-II-81 (9) was discovered from a series of six bioisosteres with significantly improved pharmacokinetic and pharmacodynamic properties as compared to 2. Oxazole 9 was further characterized and exhibited improved anxiolytic-like effects in a mouse marble burying assay and a rat Vogel conflict test.
authors.affiliation: Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Poe
authors.affiliation: Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
authors.forename: Kashi Reddy
authors.initials: KR
authors.lastname: Methuku
authors.affiliation: Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
authors.forename: Guanguan
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
authors.forename: Ashwini R
authors.initials: AR
authors.lastname: Verma
authors.affiliation: Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Teske
authors.affiliation: Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Stafford
authors.affiliation: Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
authors.forename: Leggy A
authors.initials: LA
authors.lastname: Arnold
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 42685, United States.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Cramer
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 42685, United States.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Jones
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 42685, United States.
authors.forename: Rok
authors.initials: R
authors.lastname: Cerne
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 42685, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Krambis
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 42685, United States.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Witkin
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , 28108 Alcobendas, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Jambrina
authors.affiliation: Department for Molecular Neurosciences, Medical University of Vienna , 1090 Vienna, Austria.
authors.forename: Sabah
authors.initials: S
authors.lastname: Rehman
authors.affiliation: Department for Molecular Neurosciences, Medical University of Vienna , 1090 Vienna, Austria.
authors.forename: Margot
authors.initials: M
authors.lastname: Ernst
authors.affiliation: Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 42685, United States.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Schkeryantz
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy; D001569:Benzodiazepines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000188:drug therapy; D058787:GABA-A Receptor Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D010080:Oxazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C558116:8-ethynyl-6-(2'-pyridine)-4H-2,5,10b-triazabenzo(e)azulene-3-carboxylic acid ethyl ester; D014151:Anti-Anxiety Agents; D058787:GABA-A Receptor Antagonists; D007093:Imidazoles; C000620331:KRM-II-81; D008024:Ligands; D010080:Oxazoles; D011963:Receptors, GABA-A; D001569:Benzodiazepines