SCH-C (SCH 351125), An Orally Bioavailable, Small Molecule Antagonist of the Chemokine Receptor CCR5, is a Potent Inhibitor of HIV-1 Infection in vitro and in vivo

• Published in: Proceedings of the National Academy of Sciences - PNAS 2001-10, Vol.98 (22), p.12718-12723
• Main Authors: Strizki, Julie M., Xu, Serena, Wagner, Nicole E., Wojcik, Lisa, Liu, Jia, Hou, Yan, Endres, Michael, Palani, Anandan, Shapiro, Sherry, Clader, John W., Greenlee, William J., Tagat, Jayaram R., McCombie, Stuart, Cox, Kathleen, Fawzi, Ahmad B., Chou, Chuan-Chu, Pugliese-Sivo, Catherine, Davies, Liza, Moreno, Mary E., Ho, David D., Trkola, Alexandra, Stoddart, Cheryl A., Moore, John P., Reyes, Gregory R., Baroudy, Bahige M.
• Format: Article
• Language: English
• Subjects: Acquired Immunodeficiency Syndrome - drug therapy; Animals; Anti-HIV Agents - pharmacology; Antivirals; Bioavailability; Biological Sciences; CCR5 protein; CCR5 Receptor Antagonists; Chemokine CCL5 - antagonists & inhibitors; CHO cells; CXCR4 protein; Cyclic N-Oxides - pharmacokinetics; Cyclic N-Oxides - pharmacology; Cyclic N-Oxides - therapeutic use; Drug therapy; HIV; HIV 1; HIV-1 - drug effects; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Infections; Inhibitory concentration 50; Macaca fascicularis; Male; Mice; Mice, SCID; Microbiology; Molecules; Oximes; Pharmacokinetics; Piperidines; Pyridines - pharmacokinetics; Pyridines - pharmacology; Pyridines - therapeutic use; Rats; Rats, Sprague-Dawley; Receptors; SCH 351125; SCH-C; Toxicity; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.221375398

We describe here the identification and properties of SCH-C (SCH 351125), a small molecule inhibitor of HIV-1 entry via the CCR5 coreceptor. SCH-C, an oxime-piperidine compound, is a specific CCR5 antagonist as determined in multiple receptor binding and signal transduction assays. This compound specifically inhibits HIV-1 infection mediated by CCR5 in U-87 astroglioma cells but has no effect on infection of CXCR4-expressing cells. SCH-C has broad and potent antiviral activity in vitro against primary HIV-1 isolates that use CCR5 as their entry coreceptor, with mean 50% inhibitory concentrations ranging between 0.4 and 9 nM. Moreover, SCH-C strongly inhibits the replication of an R5-using HIV-1 isolate in SCID-hu Thy/Liv mice. SCH-C has a favorable pharmacokinetic profile in rodents and primates with an oral bioavailability of 50-60% and a serum half-life of 5-6 h. On the basis of its novel mechanism of action, potent antiviral activity, and in vivo pharmacokinetic profile, SCH-C is a promising new candidate for therapeutic intervention of HIV infection.