Evaluation of the chemiluminescent nitrogen detector for solubility determinations to support drug discovery

Bhattachar, Shobha; Wesley, James A.; Seadeek, Christopher

doi:10.1016/j.jpba.2005.11.009

Cited by 46 publications

(42 citation statements)

References 6 publications

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“…19 The equimolar nitrogen response of the detector was calibrated using TRIZMA base at 28 concentrations spanning the dynamic range of the instrument from 0.08 to 4500 µg/ml nitrogen and the measured solubility values were corrected for background nitrogen. On board performance indicating standards (Imipramine HCl, Sulfamethizole and Astemizole) were used to validate assay results.…”

Section: Methodsmentioning

confidence: 99%

Exploratory analysis of kinetic solubility measurements of a small molecule library

Guha

Dexheimer

Kestranek

et al. 2011

Bioorganic & Medicinal Chemistry

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Kinetic solubility measurements using prototypical assay buffer conditions are presented for a ~58,000 member library of small molecules. Analyses of the data based upon physical and calculated properties of each individual molecule were performed and resulting trends were considered in the context of commonly held opinions of how physicochemical properties influence aqueous solubility. We further analyze the data using a decision tree model for solubility prediction and via a multi-dimensional assessment of physicochemical relationships to solubility in the context of specific ‘rule-breakers’ relative to common dogma. The role of solubility as a determinant of assay outcome is also considered based upon each compound’s cross-assay activity score for a collection of publicly available screening results. Further, the role of solubility as a governing factor for colloidal aggregation formation within a specified assay setting is examined and considered as a possible cause of a high cross-assay activity score. The results of this solubility profile should aid chemists during library design and optimization efforts and represents a useful training set for computational solubility prediction.

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Section: Methodsmentioning

confidence: 99%

Exploratory analysis of kinetic solubility measurements of a small molecule library

Guha

Dexheimer

Kestranek

et al. 2011

Bioorganic & Medicinal Chemistry

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“…Compound 1 is very lipophilic (cLogP = 5.81, chromLogD = 4.75) 21 and displays very poor solubility (19 μM) (Supporting Information, Table S2). 22 The high number of aromatic rings surely contributes to the establishment of favorable π-stacking interactions, resulting in low solubility. Not unexpectedly, R 3 quinolinyl compounds 16a – c also presented very low solubility.…”

Section: Resultsmentioning

confidence: 99%

Establishment of a Structure–Activity Relationship of 1H-Imidazo[4,5-c]quinoline-Based Kinase Inhibitor NVP-BEZ235 as a Lead for African Sleeping Sickness

et al. 2014

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Compound NVP-BEZ235 (1) is a potent inhibitor of human phospoinositide-3-kinases and mammalian target of rapamycin (mTOR) that also showed high inhibitory potency against Trypanosoma brucei cultures. With an eye toward using 1 as a starting point for anti-trypanosomal drug discovery, we report efforts to reduce host cell toxicity, to improve the physicochemical properties, and to improve the selectivity profile over human kinases. In this work, we have developed structure–activity relationships for analogues of 1 and have prepared analogues of 1 with improved solubility properties and good predicted central nervous system exposure. In this way, we have identified 4e, 9, 16e, and 16g as the most promising leads to date. We also report cell phenotype and phospholipidomic studies that suggest that these compounds exert their anti-trypanosomal effects, at least in part, by inhibition of lipid kinases.

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“…LC-CLND has been extensively used in the field of drug discovery, in quality assessment of combinatorial libraries [5,15,16] and in solubility determinations [17]. In forensic chemistry, our group was able to directly quantify the active components of seized street drug samples at an accuracy better than 11% without using primary reference standards [7].…”

Section: Resultsmentioning

confidence: 99%

Single-calibrant quantification of drugs in plasma and whole blood by liquid chromatography–chemiluminescence nitrogen detection

Ojanperä

Tuominen

Ojanperä

2007

Journal of Chromatography B

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Evaluation of the chemiluminescent nitrogen detector for solubility determinations to support drug discovery

Cited by 46 publications

References 6 publications

Exploratory analysis of kinetic solubility measurements of a small molecule library

Exploratory analysis of kinetic solubility measurements of a small molecule library

Establishment of a Structure–Activity Relationship of 1H-Imidazo[4,5-c]quinoline-Based Kinase Inhibitor NVP-BEZ235 as a Lead for African Sleeping Sickness

Single-calibrant quantification of drugs in plasma and whole blood by liquid chromatography–chemiluminescence nitrogen detection

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