Nonnucleoside reverse transcriptase inhibitors that potently and specifically block human immunodeficiency virus type 1 replication.
Certain bis(heteroaryl)piperazines (BHAPs) are potent inhibitors of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) at concentrations lower by 2-4 orders of magnitude than that which inhibits normal cellular DNA polymerase activity. Combination of a BHAP with nucleoside analog HIV-1 RT inhibitors suggested that together these compounds inhibited RT synergistically. In three human lymphocytic cell systems using several laboratory and clinical HIV-1 isolates, the BHAPs blocked HIV-1 replication with potencies nearly identical to those of 3'-azido-2',3'-dideoxythymidine or 2',3'-dideoxyadenosine; in primary cultures of human peripheral blood mononuclear cells, concentrations of these antiviral agents were lower by at least 3-4 orders of magnitude than cytotoxic levels. The BHAPs do not inhibit replication of HIV-2, the simian or feline immunodeficiency virus, or Rauscher murine leukemia virus in culture. Evaluation of a BHAP in HIV-1-infected SCID-hu mice (severe combined immunodeficient mice implanted with human fetal lymph node) showed that the compound could block HIV-1 replication in vivo. The BHAPs are readily obtained synthetically and have been extensively characterized in preclinical evaluations. These compounds hold promise for the treatment of HIV-1 infection.
Romero
D L
DL
Upjohn Laboratories, Kalamazoo, MI 49001-0199.
Busso
M
M
Tan
C K
CK
Reusser
F
F
Palmer
J R
JR
Poppe
S M
SM
Aristoff
P A
PA
Downey
K M
KM
So
A G
AG
Resnick
L
L
D000818:Animals; D000998:Antiviral Agents; D002470:Cell Survival / Q000187:drug effects; D004279:DNA, Viral / Q000032:analysis; D054306:Dideoxynucleotides; D004357:Drug Synergism; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D051379:Mice; D008819:Mice, Nude; D010879:Piperazines / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D012367:RNA, Viral / Q000032:analysis; D018894:Reverse Transcriptase Inhibitors; D013942:Thymine Nucleotides / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology
D000998:Antiviral Agents; D004279:DNA, Viral; D054306:Dideoxynucleotides; D010879:Piperazines; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D013942:Thymine Nucleotides; D015215:Zidovudine; C017216:2',3'-dideoxythymidine triphosphate