PROFILE OF CGP-61755 - A NOVEL AND POTENT HIV-1 PROTEASE INHIBITOR THAT SHOWS ENHANCED ANTI-HIV ACTIVITY WHEN COMBINED WITH OTHER ANTIRETROVIRAL AGENTS IN-VITRO

CGP 61755 is a novel hydroxyethylene derivative produced by a high yie ld 10 step chemical synthesis. It is highly specific for HIV-1 proteas e with an IC50 of 1 nM. The ED(90) in MT-2, PBLs and macrophages infec ted with laboratory strains of HIV-1 or clinical isolates is 30-100 nM . In chronically infected macrophages the ED(90) is 1000 nM (1000 nM f or saquinavir and 10 mu M for indinavir). When the antiviral activity of CGP 61755 on HIV-1 infected lymphocytes was examined using serum fr ee medium an ED(99) of 60 nM was determined, while in the presence of 10% human serum the same activity was achieved with 120 nM. When exami ned in combination with RT inhibitors or protease inhibitors, either i n a co-culture of CEM-SS and chronically infected H9IIIB cells or in a free virus lymphocyte infection, cooperativity of the antiviral activ ities was observed. Dog pharmacokinetic studies comparing p.o. and i.v . data indicate that CGP 61755 has a bioavailability between 50 and 80 %. Following oral administration the area under the concentration curv e (AUG) values increased in a dose proportional manner. The plasma lev els of the drug at 6 hours after oral administration were above the ED (90) Based on these properties we believe that CGP 61755 has an attrac tive profile that justifies further preclinical evaluation of the drug .