Piperazine-based CCR5 Antagonists as HIV-1 Inhibitors. IV. Discovery of 1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]- 4-[4-[2-methoxy-1(R)-4-(trifluoromethyl)phenyl]ethyl-3(S)-methyl-1-piperazinyl]- 4-methylpiperidine (Sch-417690/Sch-D), a Potent, Highly Selective, and Orally Bioavailable CCR5 Antagonist

J Med Chem. 2004 May 6;47(10):2405-8. doi: 10.1021/jm0304515.

Abstract

The nature and the size of the benzylic substituent are shown to be the key to controlling receptor selectivity (CCR5 vs M1, M2) and potency in the title compounds. Optimization of the lead benzylic methyl compound 3 led to the methoxymethyl analogue 30, which had excellent receptor selectivity and oral bioavailability in rats and monkeys. Compound 30 (Sch-417690/Sch-D), a potent inhibitor of HIV-1 entry into target cells, is currently in clinical trials.

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-HIV Agents / adverse effects
  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / pharmacology
  • Biological Availability
  • Brain / drug effects
  • CCR5 Receptor Antagonists*
  • Cation Transport Proteins / drug effects
  • Digestive System / drug effects
  • Ether-A-Go-Go Potassium Channels
  • HIV-1 / drug effects*
  • HIV-1 / isolation & purification
  • Humans
  • In Vitro Techniques
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / virology
  • Macaca fascicularis
  • Piperazines / adverse effects
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / pharmacology
  • Potassium Channels / drug effects
  • Potassium Channels, Voltage-Gated*
  • Pyrimidines / adverse effects
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Anti-HIV Agents
  • CCR5 Receptor Antagonists
  • Cation Transport Proteins
  • Ether-A-Go-Go Potassium Channels
  • KCNH6 protein, human
  • Piperazines
  • Piperidines
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • Pyrimidines
  • vicriviroc