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.
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.
D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens / Q000378:metabolism*; D004285:Dogs; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D007262:Infusions, Intravenous; D008252:Macaca fascicularis; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors
C544973:1-(4-benozylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione; D019380:Anti-HIV Agents; C477855:BMS-378806; D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D007211:Indoles; D010879:Piperazines; D019718:Receptors, CXCR4