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.
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.
Catalano
John G
JG
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
Gudmundsson
Kristjan S
KS
Svolto
Angilique
A
Boggs
Sharon D
SD
Miller
John F
JF
Spaltenstein
Andrew
A
Thomson
Michael
M
Wheelan
Pat
P
Minick
Doug J
DJ
Phelps
Dean P
DP
Jenkinson
Stephen
S
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
D019380:Anti-HIV Agents; D010618:Phenanthrolines; D019718:Receptors, CXCR4; C025205:1,10-phenanthroline