The design of 8-hydroxyquinoline tetracyclic lactams as HIV-1 integrase strand transfer inhibitors.
A novel series of HIV-1 integrase strand transfer inhibitors were designed using the venerable two-metal binding pharmacophore model and incorporating structural elements from two different literature scaffolds. This manuscript describes a number of 8-hydroxyquinoline tetracyclic lactams with exceptional antiviral activity against HIV-1 and little loss of potency against the IN signature resistance mutations Q148K and G140S/Q148H.
GlaxoSmithKline Research & Development, Infectious Diseases Therapeutic Area Unit, Five Moore Drive, Research Triangle Park, NC 27709, United States. Electronic address: emile.j.velthuisen@gsk.com.
Emile J
EJ
Velthuisen
GlaxoSmithKline Research & Development, Infectious Diseases Therapeutic Area Unit, Five Moore Drive, Research Triangle Park, NC 27709, United States.
Brian A
BA
Johns
GlaxoSmithKline Research & Development, Infectious Diseases Therapeutic Area Unit, Five Moore Drive, Research Triangle Park, NC 27709, United States.
David P
DP
Temelkoff
GlaxoSmithKline Research & Development, Infectious Diseases Therapeutic Area Unit, Five Moore Drive, Research Triangle Park, NC 27709, United States.
Kevin W
KW
Brown
GlaxoSmithKline Research & Development, Infectious Diseases Therapeutic Area Unit, Five Moore Drive, Research Triangle Park, NC 27709, United States.
Susan C
SC
Danehower
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002460:Cell Line; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D019427:HIV Integrase / Q000187:drug effects; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis* / Q000494:pharmacology; D009154:Mutation
D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D007769:Lactams; D019427:HIV Integrase
AIDS; HIV; Integrase; Integrase inhibitor; Quinoline; Strand transfer inhibitor