An integrated process for measuring the physicochemical properties of drug candidates in a preclinical discovery environment

Kibbey, Christopher E.; Poole, Salwa K.; Robinson, Ben; Jackson, Jean; Durham, Douglas

doi:10.1002/jps.1070

Cited by 98 publications

(63 citation statements)

References 22 publications

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“…Hopefully, with optimisations and further analytical refinements, molecular apparatus of this kind can become routine instruments of investigation in many fields, in which physicochemical phenomena dependent on pH and characterised by a spectral change have to be studied (e.g., determination of stability and pK a in highthroughput physicochemical profiling in pharmaceutical analysis). [25] In the light of this new application, a useful classification of KMDs can be done (Figure 3). In Figure 3 [14] and molecular titrators [2] (for example, [1.1.1]cryptand) and VTKMDs include temperature programmers [15] (for example, acetic anhydride).…”

mentioning

confidence: 99%

Molecular Apparatus for Automatic Titrations

Alibrandi

Vecchio

Villari

et al. 2010

Chemistry A European J

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mentioning

confidence: 99%

Molecular Apparatus for Automatic Titrations

Alibrandi

Vecchio

Villari

et al. 2010

Chemistry A European J

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“…ultidrug resistance (MDR) in Gram-negative pathogens, including Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter spp., and Stenotrophomonas maltophilia, poses a significant threat to the effective treatment of infections caused by these organisms (1)(2)(3)(4). The MDR threat has been exacerbated by the recent decrease in commercial efforts to discover and develop new antibacterial agents.…”

mentioning

confidence: 99%

Characterization of a Novel Pyranopyridine Inhibitor of the AcrAB Efflux Pump of Escherichia coli

Opperman

Kwasny

Kim

et al. 2014

Antimicrob Agents Chemother

163

153

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cMembers of the resistance-nodulation-division (RND) family of efflux pumps, such as AcrAB-TolC of Escherichia coli, play major roles in multidrug resistance (MDR) in Gram-negative bacteria. A strategy for combating MDR is to develop efflux pump inhibitors (EPIs) for use in combination with an antibacterial agent. Here, we describe MBX2319, a novel pyranopyridine EPI with potent activity against RND efflux pumps of the Enterobacteriaceae. MBX2319 decreased the MICs of ciprofloxacin (CIP), levofloxacin, and piperacillin versus E. coli AB1157 by 2-, 4-, and 8-fold, respectively, but did not exhibit antibacterial activity alone and was not active against AcrAB-TolC-deficient strains. MBX2319 (3.13 M) in combination with 0.016 g/ml CIP (minimally bactericidal) decreased the viability (CFU/ml) of E. coli AB1157 by 10,000-fold after 4 h of exposure, in comparison with 0.016 g/ml CIP alone. In contrast, phenyl-arginine-␤-naphthylamide (PA␤N), a known EPI, did not increase the bactericidal activity of 0.016 g/ml CIP at concentrations as high as 100 M. MBX2319 increased intracellular accumulation of the fluorescent dye Hoechst 33342 in wild-type but not AcrAB-TolC-deficient strains and did not perturb the transmembrane proton gradient. MBX2319 was broadly active against Enterobacteriaceae species and Pseudomonas aeruginosa. MBX2319 is a potent EPI with possible utility as an adjunctive therapeutic agent for the treatment of infections caused by Gram-negative pathogens. Multidrug resistance (MDR) in Gram-negative pathogens, including Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter spp., and Stenotrophomonas maltophilia, poses a significant threat to the effective treatment of infections caused by these organisms (1-4). The MDR threat has been exacerbated by the recent decrease in commercial efforts to discover and develop new antibacterial agents. In addition, antibacterial agents that have been introduced recently into the clinic or are in development, such as daptomycin, gemifloxacin, telithromycin, and telavancin, are not active against Gram-negative pathogens. Recently FDAapproved agents with activity against Gram-negative bacteria include tigecycline and doripenem. While tigecycline is active against bacteria producing a tetracycline-specific pump in vitro, it is pumped out rapidly by the ubiquitous multidrug pumps, and its pharmacokinetic properties limit its use for treating urinary tract infections (UTIs) and bloodstream infections (5), as will the evolution of resistance during therapy (6). Clearly, novel strategies for effectively treating infections caused by MDR Gram-negative pathogens are urgently needed.The MDR phenotype has been attributed to both acquired and intrinsic mechanisms of resistance. However, the resistance-nodulation-division (RND) efflux pumps of Gram-negative bacteria play a major role in MDR. Because of their broad substrate specificity, overexpression of these efflux pumps results in decreased susceptibility to a diverse array of antibacterial agents and biocides (7). The major ef...

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“…Along with their pharmacodynamic profile, ligands of putative pharmacological significance must be investigated also for their physicochemical features such as solubility, lipophilicity, hydrogen bonding capacity and charge, which affect their in vivo pharmacokinetic behaviour. The above mentioned parameters are easily calculated from the acidic dissociation constant of a compound under study, and the knowledge of pK a values is crucial in view of predicting the interactions of small molecules with their protein counterpart [11,12]. In addition, biologically active derivatives are often fully or partially ionized at physiological pH and the presence of ionisable groups is often essential in directing their pharmacological response.…”

Section: Introductionmentioning

confidence: 99%

Determination of Acid Dissociation Constants of Poorly Water-Soluble Nicotinic Ligands by Means of Electrophoretic and Potentiometric Techniques

Roda¹,

Dallanoce²,

Gambaro³

et al. 2015

Pharm Anal Acta

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Objectives: Acid-base dissociations constants of a series of poorly water-soluble nicotinic ligands designed as anti-inflammatory agents were determined in order to characterize the pharmacokinetic profile of this kind of ligands.Methods: pK a s values were assessed by means of potentiometric and electrophoretic methods and investigated by computational protocols.Results: Both electrophoretic and potentiometric measurements produced reliable results. However, with the electrophoretic technique only an average value for close pK a s was found, whereas the potentiometric method allowed determination of each pK a value in water-cosolvent mixtures. A theoretical treatment with various prediction programs -i.e. ADME Boxes v. 4.1, ACD/pK a DB and ACD/pK a GALAS -led in most cases to values which were not in accordance with the experimental ones. Conclusion:Electrophoretic and potentiometric techniques showed complementary features. Indeed, with capillary electrophoresis, the problem associated with the low water solubility of the studied samples could be easily overcome, although this technique did not allow to measuring all dissociation constants. In contrast, application of the potentiometric method afforded all the theoretical pK a values, although we had to perform the titrations in watercosolvent mixtures, a less precise, more laborious and time-consuming approach.

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An integrated process for measuring the physicochemical properties of drug candidates in a preclinical discovery environment

Cited by 98 publications

References 22 publications

Molecular Apparatus for Automatic Titrations

Molecular Apparatus for Automatic Titrations

Characterization of a Novel Pyranopyridine Inhibitor of the AcrAB Efflux Pump of Escherichia coli

Determination of Acid Dissociation Constants of Poorly Water-Soluble Nicotinic Ligands by Means of Electrophoretic and Potentiometric Techniques

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