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.
Lazdins
J K
JK
CIBA, Pharma Research, Basel.
Bold
G
G
Capraro
H G
HG
Cozens
R
R
Fässler
A
A
Flesch
G
G
Klimkait
T
T
Lang
M
M
Mestan
J
J
Poncioni
B
B
Rösel
J
J
Stover
D
D
Tintelnot-Blomley
M
M
Walker
M R
MR
Woods-Cook
K
K
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