Daluge SM, Good SS, Martin MT, Tibbels SR, Miller WH, Averett DR, St Clair MH, Ayers KM; Interscience Conference on Antimicrobial Agents and Chemotherapy.

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 1994 Oct 4-7; 7.

Wellcome Research Laboratories, Research Triangle Park, NC.

(IS,4R)-4-[2-Amino-6-(cyclopropylamino)-9H-purin-9-Yl]-2- cyclopentene-1-methanol (1592U89) succinate is an attractive candidate for clinical evaluation in HIV-infected patients. 1592U89 was equivalent in potency to AZT when tested in vitro in human peripheral blood lymphocytes against fresh clinical isolates of HIV-1 from AZT-naive patients (average IC50 value 0.26 micromolar for 1592U89 and 0.23 micromolar for AZT). 1592U89 demonstrated synergistic activity against HIV-1 when tested in combination with AZT, ddI, or ddC. 1592U89 is activated intracellularly to (-)-carbovir triphosphate (CBV-TP) by a novel mechanism. The K(i) value (0.021 micromolar) of CBV-TP for HIV-1 reverse transcriptase in 330-, 16,000-, 670-, and 19,000-fold lower than the K(i) values measured for human DNA polymerases alpha, beta, gamma and epsilon, respectively, when assayed under identical conditions using activated calf thymus DNA as the nucleic acid substrate. In an in vitro assay for toxicity to human red blood cell precursors, the IC50 value of 1592U89 (100 micromolar) was 300-fold greater than that of AZT. Pharmacokinetic evaluation showed good oral bioavailability (92% in mice, 77% in monkeys) in the anticipated therapeutic dose range. Penetration of 1592U89 into monkey CSF and rat brain was comparable to that of AZT, with a lack of demonstrable CNS effects. When 1592U89 succinate was given to cynomolgus monkeys for 28 days (50, 140, or 420 mg/kg/day, p.o.), drug-related findings were limited to mild, reversible increases in serum triglycerides (mid and high doses) and slight, reversible increases in liver weights (high dose only). No treatment-related changes were seen in any other monitored parameter, including neurophysiologic assessments. 1592U89 shows promise as a safe and efficacious treatment for HIV infection.

Publication Types:

• Meeting Abstracts

Keywords:

• AIDS Vaccines
• Acquired Immunodeficiency Syndrome
• Animals
• Deoxyguanine Nucleotides
• Didanosine
• Dideoxynucleosides
• HIV Infections
• HIV Seropositivity
• HIV-1
• Humans
• In Vitro
• Mice
• Rats
• Succinates
• Succinic Acid
• Zalcitabine
• Zidovudine
• abacavir
• carbovir triphosphate
• reverse transcriptase, Human immunodeficiency virus 1

Other ID:

• 95920688

UI: 102213637

From Meeting Abstracts