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Biological properties of a class potent, novel inhibitors of the HIV-1 aspartyl protease.
Livingston DJ; Pazhamisamy S; Stuver C; Lauffer L; Tung RD; Vertex
December 30, 1995
Natl Conf Hum Retroviruses Relat Infect (1st). 1993 Dec 12-16;:129.

We have developed an extremely potent (Ki less than or equal to 1 nM) series of non-peptidal inhibitors of the HIV-1 aspartyl protease and have characterized these compounds with respect to their antiviral properties, pharmacokinetics and bioavailability. Infection of various host cell lines with laboratory strains and patient isolates of HIV-1 and HIV-2 have been examined in the presence of the inhibitors. The host cell lines used for studying inhibition of infection include the T-cell lines CEM, MT4, MOLT4, and Jurkat, as well as monocytic lines. These compounds display IC90S for inhibition of infection in the range of 10-1000 nM, with very high therapeutic indexes. Pharmacokinetics of these compounds in rodent and non-human primate species show clearance half lives of 1 to 2 hours, and oral absorption studies indicate 5-25% bioavailability. Since several protease inhibitors in clinical development have sub-optimal pharmacokinetics and bioavailability, the class of compounds described here merit consideration for clinical development.

*Computer-Aided Design Crystallography, X-Ray *Drug Design HIV Protease Inhibitors/*CHEMISTRY/PHARMACOLOGY HIV-1/ENZYMOLOGY Urea/*CHEMISTRY/PHARMACOLOGY ABSTRACT