A-74704, A-77003 and A-80987 were experimental protease inhibitors developed by Abbott.

None of these drugs is currently being pursued. A-74704 was an early compound tested by Abbott which never made it into human studies. A-77003, a compound which was active against HIV at lower concentrations, was tested in a phase I study which found no evidence of antiviral effects. The drug was metabolised so quickly that it had to be given by continuous intravenous infusion. A-80987 was better absorbed, but had poor antiviral activity and caused liver toxicities in a phase I study in France and the Netherlands.

Key research

Danner reported that in a Phase I trial of A-77003 as a 24-hour infusion, the drug was very rapidly cleared from the body, such that the half-life was immeasurable. No clear antiviral effects could be detected.

Robins reported the isolation of HIV-1 mutations that are 5-10 fold resistant to A-77003 and A-80987 in vitro. Both resistant mutants shared substitutions at codons 32 and 46, of which 32 was identified as the primary mutation responsible for resistance.

Bilello reported that the lack of activity of A-80987 in vivo resulted from the binding of alpha_1- acid glycoprotein (AGP) to the drug, preventing its uptake into cells.

References

Bilello JA et a. The uptake and anti-HIV activity of A80987 is inhibited by alpha_1- acid glycoprotein in vitro. 2nd Natl Conf on Human Retroviruses, Washington, abstract 94, 1995.

Danner SA et al. Phase-1 study of A-77003, a HIV protease inhibitor, in man. 9^th Intl Conf AIDS, Berlin, abstract B26-6, 1993.

Robins T et al. Isolation and characterisation of HIV-1 mutants resistant to HIV-1 protease inhibitors. 1^st Natl Conf on Human Retroviruses, Washington, abstract 267, 1993.