ABT-538 is a Potent Inhibitor of Human Immunodeficiency Virus Protease and Has High Oral Bioavailability in Humans

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1995 Mar 28

PMID 7708670

Citations 135

Authors

D J Kempf

K C Marsh

J F Denissen

E McDonald

S Vasavanonda

C A Flentge

B E GREEN

L FINO

C H Park

X P Kong

Affiliations

Soon will be listed here.

Abstract

Examination of the structural basis for antiviral activity, oral pharmacokinetics, and hepatic metabolism among a series of symmetry-based inhibitors of the human immunodeficiency virus (HIV) protease led to the discovery of ABT-538, a promising experimental drug for the therapeutic intervention in acquired immunodeficiency syndrome (AIDS). ABT-538 exhibited potent in vitro activity against laboratory and clinical strains of HIV-1 [50% effective concentration (EC50) = 0.022-0.13 microM] and HIV-2 (EC50 = 0.16 microM). Following a single 10-mg/kg oral dose, plasma concentrations in rat, dog, and monkey exceeded the in vitro antiviral EC50 for > 12 h. In human trials, a single 400-mg dose of ABT-538 displayed a prolonged absorption profile and achieved a peak plasma concentration in excess of 5 micrograms/ml. These findings demonstrate that high oral bioavailability can be achieved in humans with peptidomimetic inhibitors of HIV protease.

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