Inhibitors of HIV-1 attachment. Part 7: Indole-7-carboxamides as potent and orally bioavailable antiviral agents

Yeung, Kap Sun; Qiu, Zhilei; Xue, Quifen; Fang, Haiquan; Yang, Zheng; Zadjura, Lisa; D’Arienzo, Celia; Eggers, Betsy J.; Riccardi, Keith; Shi, Pei Yong; Gong, Yi; Browning, Marc; Gao, Qi; Hansel, Steven; Santone, Kenneth S.; Lin, Ping Fang; Meanwell, Nicholas A.; Kadow, John F.

doi:10.1016/j.bmcl.2012.10.115

Cited by 49 publications

(16 citation statements)

References 15 publications

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“…Figure shows structural motifs that were widely used in earlier AIs in the series that led to the identification of BMS‐626529. The putative binding sites identified within the hydrophobic cleft in the outer domain of gp120 and the gp120 water channel/CD4:F43 binding pocket were compared against the full range of SARs for the AI series in order to determine their feasibility.…”

Section: Resultsmentioning

confidence: 99%

Homology models of the HIV‐1 attachment inhibitor BMS‐626529 bound to gp120 suggest a unique mechanism of action

et al. 2014

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HIV-1 gp120 undergoes multiple conformational changes both before and after binding to the host CD4 receptor. BMS-626529 is an attachment inhibitor (AI) in clinical development (administered as prodrug BMS-663068) that binds to HIV-1 gp120. To investigate the mechanism of action of this new class of antiretroviral compounds, we constructed homology models of unliganded HIV-1 gp120 (UNLIG), a pre-CD4 binding-intermediate conformation (pCD4), a CD4 bound-intermediate conformation (bCD4), and a CD4/co-receptor-bound gp120 (LIG) from a series of partial structures. We also describe a simple pathway illustrating the transition between these four states. Guided by the positions of BMS-626529 resistance substitutions and structure–activity relationship data for the AI series, putative binding sites for BMS-626529 were identified, supported by biochemical and biophysical data. BMS-626529 was docked into the UNLIG model and molecular dynamics simulations were used to demonstrate the thermodynamic stability of the different gp120 UNLIG/BMS-626529 models. We propose that BMS-626529 binds to the UNLIG conformation of gp120 within the structurally conserved outer domain, under the antiparallel β20–β21 sheet, and adjacent to the CD4 binding loop. Through this binding mode, BMS-626529 can inhibit both CD4-induced and CD4-independent formation of the “open state” four-stranded gp120 bridging sheet, and the subsequent formation and exposure of the chemokine co-receptor binding site. This unique mechanism of action prevents the initial interaction of HIV-1 with the host CD4+ T cell, and subsequent HIV-1 binding and entry. Our findings clarify the novel mechanism of BMS-626529, supporting its ongoing clinical development. Proteins 2015; 83:331–350. © 2014 Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 99%

Homology models of the HIV‐1 attachment inhibitor BMS‐626529 bound to gp120 suggest a unique mechanism of action

et al. 2014

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“…Failure to exclude water would lead to hydrolysis of the acid chloride to afford indole-3-carboxylic acid which is an unsuitable electrophile for nucleophilic cyanide attack. Application of our optimized method to the halogenated indoles (32-34) yielded the desired carbonylnitriles 28, 29 and 30 in lower yields (40%, 38% and 33% respectively) as predicted by Janosik et al 32 Interestingly, although Yeung et al 43 reported the substitution of the C-7 bromine substituent on an indole ring by cyanide following the addition of CuCN in DMF, we found no evidence of this substitution in our synthesis. The widely used method 19,44,45,46 for conversion of nitriles into thioamides originally introduced by Taylor and Zoltewicz, 47 was deemed suitable for our purposes to synthesize 11-14.…”

Section: Resultsmentioning

confidence: 44%

Synthesis and MRSA PK inhibitory activity of thiazole containing deoxytopsentin analogues

et al. 2014

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“…Interestingly, 7-chloroindole (entry 5) significantly impeded the formation of 15, reducing the overall yield of carbonyl nitrile 7. However, this result was still pleasing since it had been demonstrated by Yeung et al 24 that C-7 halogen displacement was possible in the presence of a nucleophilic cyanide species, which is commonly utilised in the previously described methods for carbonyl nitrile formation.…”

Section: Figmentioning

confidence: 55%

A new synthesis of versatile indolyl-3-carbonylnitriles

Veale

2015

Tetrahedron Letters

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Inhibitors of HIV-1 attachment. Part 7: Indole-7-carboxamides as potent and orally bioavailable antiviral agents

Cited by 49 publications

References 15 publications

Homology models of the HIV‐1 attachment inhibitor BMS‐626529 bound to gp120 suggest a unique mechanism of action

Homology models of the HIV‐1 attachment inhibitor BMS‐626529 bound to gp120 suggest a unique mechanism of action

Synthesis and MRSA PK inhibitory activity of thiazole containing deoxytopsentin analogues

A new synthesis of versatile indolyl-3-carbonylnitriles

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