The process of HIV-1 entry into host cells begins with the attachment of the viral envelope glycoprotein gp120 to the host cell receptor CD4.  This essential step can be inhibited by a class of indole or azaindole-oxoacetic piperazinyl benzamides.  Clinical proof-of-concept for this inhibition mechanism was achieved with the azaindole BMS-488043.  As part of the SAR development for this class of HIV-1 inhibitors, substitution at the C7 position of the early indole-based lead, 4-fluoroindole BMS-705, with amide moieties was explored.  Inhibitors incorporating heteroaryl carboxamides at C-7 exhibited pM potency in a primary cell-based assay using pseudotyped virus expressing the JRFL-envelope.  However, a simple methyl amide analog provided more favorable HLM stability and permeability which translated into improved animal pharmacokinetic properties compared to the early azaindole clinical candidate, BMS-378806.  Substantial improvement in the antiviral activity of the methyl amide against viruses in cell culture was achieved in a 4-methoxy-6-azaindole analog which possessed overall in vitro and in vivo profiles that compared favorably to BMS-488043.  In this presentation, various aspects of the SAR of the C7 amide series leading to the improved analogs, as well as in vitro profiles and animal pharmacokinetic properties of key compounds will be described.

Discovery of indole and azaindole-7-carboxamides as potent and orally bioavailable HIV attachment inhibitors

239th National Meeting (2010)

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