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. 1995 Oct;39(10):2229–2234. doi: 10.1128/aac.39.10.2229

SC-52151, a novel inhibitor of the human immunodeficiency virus protease.

M Bryant 1, D Getman 1, M Smidt 1, J Marr 1, M Clare 1, R Dillard 1, D Lansky 1, G DeCrescenzo 1, R Heintz 1, K Houseman 1, et al.
PMCID: PMC162920  PMID: 8619573

Abstract

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 combination of SC-52151 and nucleoside reverse transcriptase inhibitors synergistically inhibited HIV-1 replication without additive toxicity. An extended 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 albumin, substantially affect the antiviral potency of SC-52151. The oral bioavailability of [14C]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 observed in animals. Pharmacokinetic and metabolism studies in multiple animal species predict 20 to 30% systemic bioavailability, an elimination half-life of 1 to 2 h, and a volume of distribution of greater than 3 liters/kg in humans.

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Selected References

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  1. Agarwal N., Rich D. H. An improved cathepsin-D substrate and assay procedure. Anal Biochem. 1983 Apr 1;130(1):158–165. doi: 10.1016/0003-2697(83)90663-2. [DOI] [PubMed] [Google Scholar]
  2. Cha S. Tight-binding inhibitors-I. Kinetic behavior. Biochem Pharmacol. 1975 Dec 1;24(23):2177–2185. doi: 10.1016/0006-2952(75)90050-7. [DOI] [PubMed] [Google Scholar]
  3. DeLean A., Munson P. J., Rodbard D. Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves. Am J Physiol. 1978 Aug;235(2):E97–102. doi: 10.1152/ajpendo.1978.235.2.E97. [DOI] [PubMed] [Google Scholar]
  4. Getman D. P., DeCrescenzo G. A., Heintz R. M., Reed K. L., Talley J. J., Bryant M. L., Clare M., Houseman K. A., Marr J. J., Mueller R. A. Discovery of a novel class of potent HIV-1 protease inhibitors containing the (R)-(hydroxyethyl)urea isostere. J Med Chem. 1993 Jan 22;36(2):288–291. doi: 10.1021/jm00054a014. [DOI] [PubMed] [Google Scholar]
  5. Hartman N. R., Johns D. G., Mitsuya H. Pharmacokinetic analysis of dextran sulfate in rats as pertains to its clinical usefulness for therapy of HIV infection. AIDS Res Hum Retroviruses. 1990 Jun;6(6):805–812. doi: 10.1089/aid.1990.6.805. [DOI] [PubMed] [Google Scholar]
  6. Kageyama S., Anderson B. D., Hoesterey B. L., Hayashi H., Kiso Y., Flora K. P., Mitsuya H. Protein binding of human immunodeficiency virus protease inhibitor KNI-272 and alteration of its in vitro antiretroviral activity in the presence of high concentrations of proteins. Antimicrob Agents Chemother. 1994 May;38(5):1107–1111. doi: 10.1128/aac.38.5.1107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Kohl N. E., Emini E. A., Schleif W. A., Davis L. J., Heimbach J. C., Dixon R. A., Scolnick E. M., Sigal I. S. Active human immunodeficiency virus protease is required for viral infectivity. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4686–4690. doi: 10.1073/pnas.85.13.4686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983 Dec 16;65(1-2):55–63. doi: 10.1016/0022-1759(83)90303-4. [DOI] [PubMed] [Google Scholar]
  9. Neyts J., Andrei G., Snoeck R., Jähne G., Winkler I., Helsberg M., Balzarini J., De Clercq E. The N-7-substituted acyclic nucleoside analog 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine is a potent and selective inhibitor of herpesvirus replication. Antimicrob Agents Chemother. 1994 Dec;38(12):2710–2716. doi: 10.1128/aac.38.12.2710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Oie S., Jacobson M. A., Abrams D. I. Alpha 1-acid glycoprotein levels in AIDS patients before and after short-term treatment with zidovudine (ZDV) J Acquir Immune Defic Syndr. 1993 May;6(5):531–533. [PubMed] [Google Scholar]
  11. Prichard M. N., Shipman C., Jr A three-dimensional model to analyze drug-drug interactions. Antiviral Res. 1990 Oct-Nov;14(4-5):181–205. doi: 10.1016/0166-3542(90)90001-n. [DOI] [PubMed] [Google Scholar]
  12. Toth M. V., Marshall G. R. A simple, continuous fluorometric assay for HIV protease. Int J Pept Protein Res. 1990 Dec;36(6):544–550. doi: 10.1111/j.1399-3011.1990.tb00994.x. [DOI] [PubMed] [Google Scholar]

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