U-90152, A POTENT INHIBITOR OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REPLICATION

Bisheteroarylpiperazines are potent inhibitors of human immunodeficien cy virus type 1 (HIV-1) reverse transcriptase (RT). We describe a nove l bisheteroarylpiperazine, U-90152 )-4-[3-(1-methylethyl-amino)pyridin yl]piperazine}, which inhibited recombinant HIV-1 RT at a 50% inhibito ry concentration (IC50) of 0.26 muM (compared with IC50s of >440 muM f or DNA polymerases alpha and delta). U-90152 blocked the replication i n peripheral blood lymphocyles of 25 primary HIV-1 isolates, including variants that were highly resistant to 3'-azido-2',3'-dideoxythymidin e (AZT) or 2',3'-dideoxyinosine, with a mean 50% effective dose of 0.0 66 +/- 0.137 muM. U-90152 had low cellular cytotoxicity, causing less than 8% reduction in peripheral blood lymphocyte viability at 100 muM. In experiments assessing inhibition of the spread of HIV-1IIIB in cel l cultures, U-90152 was much more effective than AZT. When approximate ly 500 HIV-1IIIB-infected MT-4 cells were mixed 1:1,000 with uninfecte d cells, 3 muM AZT delayed the evidence of rapid viral growth for 7 da ys. In contrast, 3 muM U-90152 totally prevented the spread of HIV-1, and death and/or dilution of the original inoculum of infected cells p revented renewed viral growth after U-90152 was removed at day 24. The combination of U-90152 and AZT, each at 0.5 muM, also totally prevent ed viral spread. Finally, although the RT amino acid substitutions K10 3N (lysine 103 to asparagine) and Y181C (tyrosine 181 to cysteine), wh ich confer cross-resistance to several nonnucleoside inhibilors, also decrease the potency of U-90152, this drug retains significant activit y against these mutant RTs in vitro (IC50s, approximately 8 muM).