Piperazine-based CCR5 Antagonists as HIV-1 Inhibitors. II. Discovery of 1-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4- methyl-4-[3(S)-methyl-4-[1(S)-[4-(trifluoromethyl)phenyl]ethyl]-1-piperazinyl]- Piperidine N1-oxide (Sch-350634), an Orally Bioavailable, Potent CCR5 Antagonist

J Med Chem. 2001 Oct 11;44(21):3343-6. doi: 10.1021/jm0155401.

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.

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacokinetics
  • Anti-HIV Agents / pharmacology
  • Biological Availability
  • CCR5 Receptor Antagonists*
  • Cell Line
  • Cyclic N-Oxides / chemical synthesis*
  • 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 / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacokinetics
  • Piperazines / pharmacology
  • Rats
  • Structure-Activity Relationship

Substances

  • 1-((2,4-dimethyl-3-pyridinyl)carbonyl)-4-methyl-4-(3-methyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)-1-piperazinyl)piperidine N1-oxide
  • Anti-HIV Agents
  • CCR5 Receptor Antagonists
  • Cyclic N-Oxides
  • Piperazines