A generally applicable method for assessing the electrophilicity and reactivity of diverse nitrile-containing compounds

Oballa, Renata M.; Truchon, Jean‐Francois; Bayly, Christopher I.; Chauret, Nathalie; Day, Stephen H.; Crane, Sheldon N.; Berthelette, Carl

doi:10.1016/j.bmcl.2006.11.044

Cited by 137 publications

(132 citation statements)

References 29 publications

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“…The reactivity of compounds 3 and 5 against thiol nucleophiles was evaluated according to literature procedures. 55,56 While for the acrylamide derivative 3 significant formation of conjugates was detected in the presence of cysteamine, glutathione (GSH), and N-acetylcysteine (NAC) ( Table 3 and Supporting Information, Figure S2), compound 5 gave no measurable adducts with thiol derivatives up to 24 h of incubation. Table S1).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…The formation of conjugates with cysteine added in molar excess (2 mM) was evaluated in cell lysate by LC−HRMS employing an LTQ-Orbitrap mass analyzer. 56 Compound 3 quickly reacted with the thiol derivative to form the corresponding cysteine conjugate (data not shown). When compound 5 was added to the cell lysate containing cysteine, a peak corresponding to the acrylamide derivative 3 was detected after 1 h ([M + H] + = 369.03, t R = 8.87; Figure 3A), as well as a peak corresponding to the adduct of cysteine to the acrylamide fragment ([M + H] + = 490.05, t R = 6.61 min; Figure 3B).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides

et al. 2012

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Irreversible epidermal growth factor receptor (EGFR) inhibitors contain a reactive warhead which covalently interacts with a conserved cysteine residue in the kinase domain. The acrylamide fragment, a commonly employed warhead, effectively alkylates Cys797 of EGFR, but its reactivity can cause rapid metabolic deactivation or nonspecific reactions with offtargets. We describe here a new series of irreversible inhibitors containing a 3-aminopropanamide linked in position 6 to 4-anilinoquinazoline or 4-anilinoquinoline-3-carbonitrile driving portions. Some of these compounds proved to be as efficient as their acrylamide analogues in inhibiting EGFR-TK (TK = tyrosine kinase) autophosphorylation in A549 lung cancer cells. Moreover, several 3-aminopropanamides suppressed proliferation of gefitinib-resistant H1975 cells, harboring the T790M mutation in EGFR, at significantly lower concentrations than did gefitinib. A prototypical compound, N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(dimethylamino)propanamide (5), did not show covalent binding to cell-free EGFR-TK in a fluorescence assay, while it underwent selective activation in the intracellular environment, releasing an acrylamide derivative which can react with thiol groups.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides

et al. 2012

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“…Oballa et al, hypothesized that the increased electrophilicity of the nitrile moiety could impact the reversibility of enzyme-inhibitor complex formation [99]. According to their calculated reactivities, aryl nitriles, particularly triazine and pyrimidine nitriles, should possess the most reactive nitrile moieties.…”

Section: Nitrilesmentioning

confidence: 98%

Falcipain Inhibition as a Promising Antimalarial Target

Marco¹,

Coteron

2012

CTMC

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Falcipains are Plasmodium falciparum cysteine proteases involved in different processes of the erythrocytic cycle of the malaria parasite like hydrolysis of host hemoglobin, erythrocyte invasion, and erythrocyte rupture. These proteases constitute promising targets in the search for novel therapies that would ease the burden caused by the increasing resistance to current antimalarial drugs. Despite biochemical characterization of four falcipains so far, the search for new falcipain inhibitors has been limited to falcipain-2 and/ or falcipain-3, due to their interesting hemoglobinase capacity and the ample availability of tools to study them. We describe progress towards the discovery of promising falcipain inhibitors, in the light of their drug-like properties and the effect of the inhibition of several of these cysteine proteases. Some important aspects to focus on future development of falcipain inhibition are also discussed.

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“…However, as is true for ketones, there can be profound differences in the electrophilicity of the nitrile moieties [115]. Whereas a-amidoacetonitriles, such as balicatib (3) and L-873724 (6), were shown to have intermediate electrophilicity, pyrimidine-based derivatives (cf.…”

Section: Expert Opinionmentioning

confidence: 99%

Inhibitors of cathepsin K: a patent review (2004 – 2010)

Wijkmans

Gossen

2011

Expert Opinion on Therapeutic Patents

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Between 2004 and 2010, more than 50 patent applications have appeared, underlining the continued interest in small molecule cathepsin K inhibition for therapeutic intervention. Most compounds claimed are peptide-derived inhibitors displaying a reversible binding nitrile or ketone warhead. The success of these compounds in the clinic will be determined by the selectivity that can be achieved against other off-target cathepsin. In this respect, eliminating lysosomotropic characteristics may prove to be crucial in the design of selective cathepsin K inhibitors. During the review period, ONO-5334 and odanacatib have progressed to Phase II and Phase III clinical trials, respectively. The results of these studies are eagerly awaited and may determine the future of these agents as disease-modifying therapeutics.

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A generally applicable method for assessing the electrophilicity and reactivity of diverse nitrile-containing compounds

Cited by 137 publications

References 29 publications

Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides

Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides

Falcipain Inhibition as a Promising Antimalarial Target

Inhibitors of cathepsin K: a patent review (2004 – 2010)

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