ABSTRACT
Truncation of the original piperidino-2(S)-methyl piperazine lead structure 2, from a family of muscarinic antagonists, gave compound 8 which has improved selectivity for the HIV-1 co-receptor CCR5 over muscarinic receptors. Further optimization for pharmacokinetic properties afforded Sch-350634 (1), a prototypical piperazine-based CCR5 antagonist, which is a potent inhibitor of HIV-1 entry and replication in PBMCs. The title compound (1) has excellent oral bioavailability in rat, dog, and monkey.
Subject(s)
Anti-HIV Agents/chemical synthesis , CCR5 Receptor Antagonists , Cyclic N-Oxides/chemical synthesis , Piperazines/chemical synthesis , Administration, Oral , Animals , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/pharmacology , Biological Availability , Cell Line , Cyclic N-Oxides/chemistry , Cyclic N-Oxides/pharmacokinetics , Cyclic N-Oxides/pharmacology , Dogs , HIV-1/drug effects , In Vitro Techniques , Leukocytes, Mononuclear/virology , Macaca fascicularis , Piperazines/chemistry , Piperazines/pharmacokinetics , Piperazines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Acquired Immunodeficiency Syndrome/drug therapy , Anti-HIV Agents/pharmacology , CCR5 Receptor Antagonists , Cyclic N-Oxides/pharmacology , HIV-1/drug effects , Piperidines , Pyridines/pharmacology , Animals , Chemokine CCL5/antagonists & inhibitors , Cyclic N-Oxides/pharmacokinetics , Cyclic N-Oxides/therapeutic use , Humans , Macaca fascicularis , Male , Mice , Mice, SCID , Oximes , Pyridines/pharmacokinetics , Pyridines/therapeutic use , Rats , Rats, Sprague-DawleyABSTRACT
Optimization of the piperidino-piperazines 1 and 2 provided early leads 3 and 4, which showed good activity in the CCR5-RANTES binding assay and in antiviral assays. A systematic study around these structures showed that the 2(S)-methyl piperazine is essential for CCR5 affinity, which is further enhanced by forming the 2,6-dimethyl benzamide of the piperidine.
Subject(s)
Anti-HIV Agents/pharmacology , CCR5 Receptor Antagonists , HIV-1/drug effects , Piperazines/pharmacology , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Microbial Sensitivity Tests , Piperazines/chemistry , Structure-Activity RelationshipABSTRACT
The potential toxicological liabilities of the M(2) muscarinic antagonist 1 were addressed by replacing the methylenedioxyphenyl moiety with a p-methoxyphenyl group, resulting in M(2) selective compounds such as 3. Several halogenated naphthamide derivatives of 3 were studied in order to improve the pharmacokinetic profile via blockage of oxidative metabolism. Compound 4 demonstrated excellent M(2) affinity and selectivity, human microsomal stability, and oral bioavailability in rodents and primates.