SC-52151, A NOVEL INHIBITOR OF THE HUMAN-IMMUNODEFICIENCY-VIRUS PROTEASE

SC-52151 is a potent, selective, tight-binding human immunodeficiency virus (HIV) protease inhibitor containing the novel (R)-(hydroxyethyl) urea isostere. The mean 50% effective concentration for lymphotropic, monocytotropic strains and field isolates of HIV type 1 (HIV-1), HIV- 2, and simian immunodeficiency virus is 26 ng/ml (43 nM). The combinat ion of SC-52151 and nucleoside reverse transcriptase inhibitors synerg istically inhibited HIV-1 replication without additive toxicity. An ex tended postantiviral effect correlates with inhibition of gag and gag- pol polyprotein processing, SC-52151 is highly protein bound (>90%) in human plasma, and the level of partitioning into erythrocytes is low, Physiological concentrations of alpha-1-acid glycoprotein, but not al bumin, substantially affect the antiviral potency of SC-52151, The ora l bioavailability of [C-14]SC-52151 is 17% when it is administered as an elixir to the rat, dog, or monkey, Oxidation of the t-butyl moiety is the major route of biotransformation, and elimination is mainly by biliary excretion, No toxicologically significant effects have been ob served in animals, Pharmacokinetic and metabolism studies in multiple animal species predict 20 to 30% systemic bioavailability, an eliminat ion half-life of 1 to 2 h, and a volume of distribution of greater tha n 3 liters/kg in humans.