Inhibitors of Human Immunodeficiency Virus Type 1 (HIV-1) Attachment. 5. An Evolution from Indole to Azaindoles Leading to the Discovery of 1-(4-Benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-488043), a Drug Candidate That Demonstrates Antiviral Activity in HIV-1-Infected Subjects

Abstract

Azaindole derivatives derived from the screening lead 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (1) were prepared and characterized to assess their potential as inhibitors of HIV-1 attachment. Systematic replacement of each of the unfused carbon atoms in the phenyl ring of the indole moiety by a nitrogen atom provided four different azaindole derivatives that displayed a clear SAR for antiviral activity and all of which displayed marked improvements in pharmaceutical properties. Optimization of these azaindole leads resulted in the identification of two compounds that were advanced to clinical studies: (R)-1-(4-benzoyl-2-methylpiperazin-1-yl)-2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethane-1,2-dione (BMS-377806, 3) and 1-(4-benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-488043, 4). In a preliminary clinical study, 4 administered as monotherapy for 8 days, reduced viremia in HIV-1-infected subjects, providing proof of concept for this mechanistic class.

In Vivo Patterns of Resistance to the HIV Attachment Inhibitor BMS-488043

“…However, BMS-378806 failed to achieve targeted plasma exposures in humans. Therefore, a related compound, BMS-488043, with improved in vitro antiviral activity and pharmacokinetic properties was advanced into clinical development (1,23,30,33). Taken with a high-fat meal, BMS-488043 achieved a 10-fold higher concentration in the plasma of human subjects than was observed for BMS-378806.…”

Targeting HIV: Past, Present and Future

“…It is in phase II clinical development. In a preliminary clinical study, BMS-488043 administered as monotherapy for 8 days demonstrated potent antiviral activity [17]. Pfizer Inc. has two compounds (WO-2005016344 and WO-2005121094) with similar characteristics to BMS-488043.…”

Introduction

“…Compound 1 blocks HIV-1-mediated cell-cell fusion and the formation of gp41 six-helix bundles, as does enfuvirtide [15]. Small-molecule CD4 mimics with oxalamide and related substructures are another series of anti-HIV agents [16][17][18]. The representative BMS-448043 (2) exhibits subnanomolar anti-HIV activity by interaction with the CD4 binding pocket in gp120 [18].…”

“…Small-molecule CD4 mimics with oxalamide and related substructures are another series of anti-HIV agents [16][17][18]. The representative BMS-448043 (2) exhibits subnanomolar anti-HIV activity by interaction with the CD4 binding pocket in gp120 [18]. Alternatively, there are some examples of antagonists against CXC chemokine receptor type 4 (CXCR4).…”