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
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.