title: Novel design and synthesis of modified structure of carvedilol.
abstract: β-adrenergic blocking agents have been in use for nearly 40 years. β-blockers have been more thoroughly studied in the past twenty years as they have become commonly prescribed to heart failure patients. The class of β-blockers has grown considerably and has many pharmaceutical applications in patients with heart failure. Carvedilol has been the most effective beta-blocker in the treatment of the systolic heart failure. Carvedilol is a non-selective β- and α-blocker enantiomer with antioxidant effects that are attributed to its carbazole moiety. Carvedilol is taken twice daily because it is extensively metabolized and therefore loses its effectiveness due to a short half-life. Recently a long acting carvedilol has become available, as Coreg CR. Coreg CR is available for once-a-day administration as controlled-release oral capsules containing 10, 20, 40, or 80 mg carvedilol phosphate. The subject of the current report is to design a new structural analog of carvedilol that incorporates a protecting group such as a fluorine atom at position 8 of the carbazole ring for the purpose of blocking a critical metabolic pathway thus increasing its half life. This will follow discussion regarding current carvedilol patents. We believe that carvedilol activity will remain unchanged. The synthesis of 8-Fluoro-1, 2, 3, 9- tetrahydro-4H-carbazol-4-one, a key synthetic intermediate of the designed carvedilol analog, was carried out and successfully characterized.
authors.affiliation: University of Arizona Sarver, Heart Center, 1501 North Campbell Avenue, Tucson, AZ 85724, USA. mhashemzadeh@shc.arizona.edu
authors.forename: Mehrnoosh
authors.initials: M
authors.lastname: Hashemzadeh
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Movahed
authors.forename: Wade A
authors.initials: WA
authors.lastname: Russu
authors.forename: Ladan
authors.initials: L
authors.lastname: Soroush
authors.forename: Diné N
authors.initials: DN
authors.lastname: Hill
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D002227:Carbazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000077261:Carvedilol; D003692:Delayed-Action Preparations; D006207:Half-Life; D006333:Heart Failure / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D010330:Patents as Topic; D011412:Propanolamines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: C569246:8-fluoro-1,2,3,9-tetrahydro-4H-carbazol-4-one; D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D003692:Delayed-Action Preparations; D011412:Propanolamines; D000077261:Carvedilol