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

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 spe cifically inhibits HIV-1 infection mediated by CCR5 in U-87 astroglioma cel ls but has no effect on infection of CXCR4-expressing cells. SCH-C has broa d and potent antiviral activity in vitro against primary HIV-1 isolates tha t use CCR5 as their entry coreceptor, with mean 50% inhibitory concentratio ns ranging between 0.4 and 9 nM. Moreover, SCH-C strongly inhibits the repl ication of an R5-using HIV-1 isolate in SCID-hu Thy/Liv mice. SCH-C has a f avorable pharmacokinetic profile in rodents and primates with an oral bioav ailability of 50-60% and a serum half-life of 5-6 In. On the basis of its n ovel mechanism of action, potent antiviral activity, and in vivo pharmacoki netic profile, SCH-C is a promising new candidate for therapeutic intervent ion of HIV infection.