Discovery of 4-benzoyl-1-[(4-methoxy-1H- pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl]-2- (R)-methylpiperazine (BMS-378806): A Novel HIV-1 Attachment Inhibitor That Interferes With CD4-gp120 Interactions

J Med Chem. 2003 Sep 25;46(20):4236-9. doi: 10.1021/jm034082o.

Abstract

Indole derivative 1 interferes with the interaction of the HIV surface protein gp120 with the host cell receptor CD4. The 4-fluoro derivative 2 exhibited markedly enhanced potency and was bioavailable in the rat, dog, and cynomolgus monkey when administered orally as a solution formulation. However, aqueous suspensions of 2 were poorly bioavailable, indicative of dissolution-limited absorption. The 7-azaindole derivative 3, BMS-378806, exhibited improved pharmaceutical properties while retaining the HIV-1 inhibitory profile of 2.

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-HIV Agents / pharmacokinetics
  • Anti-HIV Agents / pharmacology*
  • Biological Availability
  • CCR5 Receptor Antagonists
  • CD4 Antigens / metabolism*
  • Dogs
  • HIV Envelope Protein gp120 / metabolism*
  • HIV-1 / drug effects*
  • HIV-1 / metabolism*
  • Humans
  • Indoles / chemistry
  • Indoles / pharmacokinetics
  • Indoles / pharmacology*
  • Infusions, Intravenous
  • Macaca fascicularis
  • Piperazines / chemistry
  • Piperazines / pharmacokinetics
  • Piperazines / pharmacology*
  • Rats
  • Receptors, CXCR4 / antagonists & inhibitors

Substances

  • 1-(4-benozylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione
  • Anti-HIV Agents
  • BMS-378806
  • CCR5 Receptor Antagonists
  • CD4 Antigens
  • HIV Envelope Protein gp120
  • Indoles
  • Piperazines
  • Receptors, CXCR4