Experimental solubility profiling of marketed CNS drugs, exploring solubility limit of CNS discovery candidate

Alelyunas, Yun W.; Empfield, James R.; McCarthy, Dennis J.; Spreen, Russell C.; Bui, Khanh; Pelosi-Kilby, Luciana; Shen, Cindy

doi:10.1016/j.bmcl.2010.10.068

Cited by 56 publications

(27 citation statements)

References 25 publications

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“…We suggest that for highly metabolized drugs, BBB penetration in humans can be optimized by increasing their solubility. Even if linking these two properties is not intuitive, Alelyunas et al [153] found that, starting from the experimental solubility measures for 98 marketed CNS drugs, over 85% of them are highly soluble. Other recent work [154] suggests that solubility optimization can be achieved by manipulating the molecular symmetry of the drugs.…”

Section: Integration Of Findings and Recommendationsmentioning

confidence: 99%

Improving the prediction of the brain disposition for orally administered drugs using BDDCS

Broccatelli

Larregieu

Cruciani

et al. 2012

Advanced Drug Delivery Reviews

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In modeling blood–brain barrier (BBB) passage, in silico models have yielded ~80% prediction accuracy, and are currently used in early drug discovery. Being derived from molecular structural information only, these models do not take into account the biological factors responsible for the in vivo outcome. Passive permeability and P-glycoprotein (Pgp, ABCB1) efflux have been successfully recognized to impact xenobiotic extrusion from the brain, as Pgp is known to play a role in limiting the BBB penetration of oral drugs in humans. However, these two properties alone fail to explain the BBB penetration for a significant number of marketed central nervous system (CNS) agents. The Biopharmaceutics Drug Disposition Classification System (BDDCS) has proved useful in predicting drug disposition in the human body, particularly in the liver and intestine. Here we discuss the value of using BDDCS to improve BBB predictions of oral drugs. BDDCS class membership was integrated with in vitro Pgp efflux and in silico permeability data to create a simple 3-step classification tree that accurately predicted CNS disposition for more than 90% of 153 drugs in our data set. About 98% of BDDCS class 1 drugs were found to markedly distribute throughout the brain; this includes a number of BDDCS class 1 drugs shown to be Pgp substrates. This new perspective provides a further interpretation of how Pgp influences the sedative effects of H1-histamine receptor antagonists.

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Section: Integration Of Findings and Recommendationsmentioning

confidence: 99%

Improving the prediction of the brain disposition for orally administered drugs using BDDCS

Broccatelli

Larregieu

Cruciani

et al. 2012

Advanced Drug Delivery Reviews

View full text Add to dashboard Cite

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“…The physical-chemical properties were calculated (ACDLabs PhysChem Suite 2014 [20]) and/or experimentally measured [41] for the two most potent compounds 5 and 12 and the parent compound frentizole ( Table 3). The obtained data were compared with optimal properties for CNS targeted drugs [42][43][44]. All compounds complied with the optimal values for molecular weight, H-bond acceptors/donors, number of rotatable bonds and ClogP/ElogP values.…”

Section: Resultsmentioning

confidence: 89%

6-Benzothiazolyl Ureas, Thioureas and Guanidines are Potent Inhibitors of ABAD/17β-HSD10 and Potential Drugs for Alzheimer"s Disease Treatment: Design, Synthesis and in vitro Evaluation

Benek

Hroch

Aitken

et al. 2017

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“…The solubility did not change significantly between the three time points tested, suggesting that equilibrium solubility was obtained. As a comparison, the aqueous solubility of DIAZ has previously been determined to be 0.0732 mg/mL (100 mM phosphate buffer at pH 7.4 at 25°C) …”

Section: Resultsmentioning

confidence: 99%

Azone® Decreases the Buccal Mucosal Permeation of Diazepam in a Concentration-Dependent Manner via a Reservoir Effect

Meng-Lund

Jacobsen

Jin

et al. 2014

Journal of Pharmaceutical Sciences

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Experimental solubility profiling of marketed CNS drugs, exploring solubility limit of CNS discovery candidate

Cited by 56 publications

References 25 publications

Improving the prediction of the brain disposition for orally administered drugs using BDDCS

Improving the prediction of the brain disposition for orally administered drugs using BDDCS

6-Benzothiazolyl Ureas, Thioureas and Guanidines are Potent Inhibitors of ABAD/17β-HSD10 and Potential Drugs for Alzheimer"s Disease Treatment: Design, Synthesis and in vitro Evaluation

Azone® Decreases the Buccal Mucosal Permeation of Diazepam in a Concentration-Dependent Manner via a Reservoir Effect

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