Bryant M, Smidt M, Getman D, Talley J, Vazquez M, Decrescenzo G, Mueller R, Roy A, Ng J, Stolzenbach J; National Conference on Human Retroviruses and Related Infections.

Program Abstr First Natl Conf Hum Retrovir Relat Infect Natl Conf Hum Retrovir Relat Infect 1st 1993 Wash DC. 1993 Dec 12-16; 100.

G.D. Searle/Monsanto Co.

SC-52151 is a potent, selective, tight-binding HIV protease inhibitor containing the novel (R) - (hydroxyethyl) urea isostere synthesized in 10 steps from readily available materials. The EC50 (mean) against lymphotropic, monocytropic, primary clinical isolates, HIV-2 and SIV is 43 nM. SC-52151 in combination with nucleoside analog RT inhibitors is synergistic: with ddI and ddC it is also synergistic against AZT resistant strains of HIV. A significant post-antiviral effect of greater than 8 hours correlates with irreversible inhibition of gag and gag-pol polyprotein processing. The oral bioavailability of [14C] SC-52151 is 17% when administered in solution to the rat. Oxidation of the t-butyl moiety is the major route of biotransformation in vivo and elimination is mainly by biliary excretion. Two additional metabolic pathways have been identified including, hydroxylation of the isobutyl group and N-dealkylation by removal of the isobutyl group. No toxicologically significant effects in animals have been detected at doses up to 600 mg/kg for fours and mutagenicity studies are negative. In humans, an estimate of single-dose oral bioavailability is greater than 20% and it is well tolerated at a peak plasma concentration in excess of 1500 ng/ml.

Publication Types:

• Meeting Abstracts

Keywords:

• Acquired Immunodeficiency Syndrome
• Animals
• Antiviral Agents
• Didanosine
• Gene Products, gag
• HIV
• HIV Infections
• HIV Protease
• HIV Protease Inhibitors
• HIV-2
• Humans
• Rats
• SC 52151
• Simian immunodeficiency virus
• Urea
• Zalcitabine
• Zidovudine
• reverse transcriptase, Human immunodeficiency virus 1

Other ID:

• 95921279

UI: 102214219

From Meeting Abstracts