title: Synthesis of a novel tricyclic 1,2,3,4,4a,5,6,10b-octahydro-1,10-phenanthroline ring system and CXCR4 antagonists with potent activity against HIV-1.
abstract: Stereorandom and diastereoselective syntheses of a novel 1,2,3,4,4a,5,6,10b-octahydro-1,10-phenanthroline ring system are described. Derivatives of all four diastereomers were prepared and isolated in >98% ee. The pure enantiomers were compared in order to determine the preferred absolute and relative configuration required for optimal anti-HIV activity. Anti-HIV potency and pharmacokinetic properties of the newly synthesized tricyclic octahydrophenanthroline inhibitors are presented and comparisons are made to previously reported bicyclic (8S)-N-methyl-5,6,7,8-tetrahydro-8-quinolinamine analogs.
authors.affiliation: Department of Medicinal Chemistry, Infectious Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline Research & Development, Five Moore Drive, Research Triangle Park, NC 27709-3398, USA. john.g.catalano@gsk.com
authors.forename: John G
authors.initials: JG
authors.lastname: Catalano
authors.forename: Kristjan S
authors.initials: KS
authors.lastname: Gudmundsson
authors.forename: Angilique
authors.initials: A
authors.lastname: Svolto
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Boggs
authors.forename: John F
authors.initials: JF
authors.lastname: Miller
authors.forename: Andrew
authors.initials: A
authors.lastname: Spaltenstein
authors.forename: Michael
authors.initials: M
authors.lastname: Thomson
authors.forename: Pat
authors.initials: P
authors.lastname: Wheelan
authors.forename: Doug J
authors.initials: DJ
authors.lastname: Minick
authors.forename: Dean P
authors.initials: DP
authors.lastname: Phelps
authors.forename: Stephen
authors.initials: S
authors.lastname: Jenkinson
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D004285:Dogs; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D010618:Phenanthrolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D010618:Phenanthrolines; D019718:Receptors, CXCR4; C025205:1,10-phenanthroline