5-CHLORO-2',3'-DIDEOXY-3'-FLUOROURIDINE (935U83), A SELECTIVE ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS AGENT WITH AN IMPROVED METABOLIC AND TOXICOLOGICAL PROFILE

5-Chloro-2',3'-dideoxy-3'-fluorouridine (935U83) is a selective anti-h uman immunodeficiency virus (HIV) agent. When tested in phytohemagglut inin-stimulated normal human peripheral blood lymphocytes against fres h clinical isolates of HIV type 1 (HIV-1) obtained from patients naive to AZT (3'-azido-3'-deoxythymidine [zidovudine]), 935U83 inhibited vi rus growth with an average 50% inhibitory concentration (IC50) of 1.8 mu M; corresponding IC(50)s were 0.10 mu M for FLT (3'-deoxy-3'-fluoro thymidine) and 0.23, 0.49, and 0.03 mu M for the approved agents AZT, ddI (2',3'-dideoxyinosine), and ddC (2',3'-dideoxycytosine), respectiv ely. Importantly, 935U83 retained activity against HIV strains that we re resistant to AZT, ddI, or ddC. Of additional interest, we were unab le to generate virus which was resistant to 935U83 by passaging either HXB2 (AZT-sensitive) or RTMC (AZT-resistant) strains in the presence of high concentrations of 935U83. The anabolic profile of 935U83 was s imilar to that of AZT, and 935U83 triphosphate was a potent inhibitor of HIV-1 reverse transcriptase. Pharmacokinetic evaluation showed good oral bioavailability (86% in mice and 60% in monkeys) and less extens ive metabolism to the glucuronide relative to AZT. 935U83 showed low t oxicity. In an in vitro assay for toxicity to a human erythrocyte prog enitor, erythroid burst-forming unit (BFU-E), the IC50 for 935U83 (>40 0 mu M) was more than 1,000-fold those of FLT (0.07 mu M) and AZT (0.3 0 mu M) Mild reversible reductions in erythrocytes and associated para meters were seen in mice dosed orally with 2,000 mg of 935U83 per kg p er day for 1 and 6 months. In monkeys dosed orally with up to 700 mg/k g/day for 1 and 6 months, the only possible treatment-related finding was cataracts in 1 of 12 animals given the intermediate dose of 225 mg /kg/day. At the highest doses in mice and monkeys; maximal concentrati ons in plasma were more than 100-fold the anti-HIV IC(50)s against cli nical isolates. This safety profile in animals compares very favorably with that of any of the anti-HIV drugs approved to date and has led u s to begin evaluation of 935U83 in patients with HIV infection.