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 yield 10 step chemical synthesis. It is highly specific for HIV-1 protease with an IC50 of 1 nM. The ED90 in MT-2, PBLs and macrophages is infected with laboratory strains of HIV-1 or clinical isolates is 30-100 nM. In chronically infected macrophages the ED90 is 1000 nM (1000 nM for saquinavir and 10 microM for indinavir). When the antiviral activity of CGP 61755 on HIV-1 infected lymphocytes was examined using serum free medium an ED99 of 60 nM was determined, while in the presence of 10% human serum the same activity was achieved with 120 nM. When examined in combination with RT inhibitors or protease inhibitors, either in a co-culture of CEM-SS and chronically infected H9IIIB cells or in a free virus lymphocyte infection, cooperativity of the antiviral activities 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 curve (AUC) values increased in a dose proportional manner. The plasma levels of the drug at 6 hours after oral administration were above the ED90. Based on these properties we believe that CGP 61755 has an attractive profile that justifies further preclinical evaluation of the drug.
CIBA, Pharma Research, Basel.
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Lazdins
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Bold
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Capraro
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Cozens
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Fässler
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Flesch
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Klimkait
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Lang
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Mestan
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Poncioni
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Rösel
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Stover
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Tintelnot-Blomley
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Walker
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D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D001798:Blood Proteins / Q000378:metabolism; D004285:Dogs; D005030:Ethylenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D011485:Protein Binding; D014779:Virus Replication / Q000187:drug effects*
D019380:Anti-HIV Agents; D001798:Blood Proteins; D005030:Ethylenes; D017320:HIV Protease Inhibitors; C103288:CGP 61755