Transport in QSAR III

Waterbeemd, J. Th. M. Van De; Jansen, A. C. A.; Gerritsma, K. W.

doi:10.1007/bf02273190

Cited by 5 publications

(7 citation statements)

References 18 publications

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“…A bilinear relationship was found between the log of the transfer rate constants (log k 1 and log k - 1 ) and log D (Figure ). The rate constant log k 1 is known to be thermodynamically controlled and to increase linearly with lipophilicity. ,, With further increases in lipophilicity, the diffusion of the solute becomes rate-limiting and a plateau is reached when kinetic control replaces thermodynamic control. The reverse occurs for the rate constant log k - 1 .…”

Section: Resultsmentioning

confidence: 99%

Molecular Properties and Pharmacokinetic Behavior of Cetirizine, a Zwitterionic H₁-Receptor Antagonist

et al. 1998

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The ionization and lipophilicity behavior of the antihistamine (H1-receptor antagonist) cetirizine was investigated, showing the drug to exist almost exclusively as a zwitterion in the pH region 3.5-7.5. In this pH range, its octanol/water lipophilicity is constant and low compared to cationic antihistamines (log D = log PZ = 1.5), whereas its H-bonding capacity is relatively large (delta log PZ > or = 3.1). Conformational, electronic, and lipophilicity potential calculations revealed that zwitterionic cetirizine experiences partial intramolecular charge neutralization in folded conformers of lower polarity. Pharmacokinetic investigations have shown the drug to be highly bound to blood proteins, mainly serum albumin, and to have a low brain uptake, explaining its lack of sedative effects. As such, cetirizine does not differ from "second-generation" antihistamines. In contrast, its very low apparent volume of distribution in humans (0.4 L kg-1, smaller than that of exchangeable water) implies a low affinity for lean tissues such as the myocardium and is compatible with the absence of cardiotoxicity of the drug. The zwitterionic nature and modest lipophilicity of cetirizine may account for this pharmacokinetic behavior. The suggestion is offered that cetirizine and analogous zwitterions, whose physicochemical, pharmacokinetic, and pharmacodynamic properties differ from those of "first-" and "second-generation" drugs in this class, could be considered as "third-generation" antihistamines.

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Section: Resultsmentioning

confidence: 99%

Molecular Properties and Pharmacokinetic Behavior of Cetirizine, a Zwitterionic H₁-Receptor Antagonist

et al. 1998

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“… 2110 – 2112 Equation 14 supports the previously published conclusion about the proportionality between the concentration at a given time and the product of the rate parameters of involved transport processes. ( 2083 )…”

Section: Explicit Descriptions For Multi-bilayer Systemsmentioning

confidence: 99%

“…Van de Waterbeemd described the transport in a three-compartment model with equal compartment volumes analytically. He extended the results for the initial distribution period to multiple bilayer systems and showed that the concentrations are proportional to the product of the transfer rate parameters of involved steps. , …”

Section: Numerical Simulations For Multi-bilayer Systemsmentioning

confidence: 99%

Modeling Kinetics of Subcellular Disposition of Chemicals

Baláž

2009

Chem. Rev.

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“…ammonium ions). 95 , In this interpretation, the two solvated states (organic or aqueous) are energetic wells and should be observable intermediates on the catalytic cycle. Also, a catalyst traversing the interphase is in a third state, namely a transition state, which has an infinitesimal population during the catalytic cycle.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the thermodynamic partition coefficient is expressed as the ratio of the forward ( k 1 ) and reverse ( k 2 ) rates of the catalyst traversing the interfacial region . This type of analysis allows the application of transition-state theory and is known to be an accurate representation, even for ionic solutes (e.g., ammonium ions) . In this interpretation, the two solvated states (organic or aqueous) are energetic wells and should be observable intermediates on the catalytic cycle.…”

Section: Discussionmentioning

confidence: 99%

A Systematic Investigation of Quaternary Ammonium Ions as Asymmetric Phase-Transfer Catalysts. Application of Quantitative Structure Activity/Selectivity Relationships

2011

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While the synthetic utility of asymmetric phase transfer catalysis continues to expand, the number of proven catalyst types and design criteria remains limited. At the origin of this scarcity is a lack in understanding of how catalyst structural features affect the rate and enantioselectivity of phase transfer catalyzed reactions. Described in this paper is the development of quantitative structure-activity relationships (QSAR) and -selectivity relationships (QSSR) for the alkylation of a protected glycine imine with libraries of quaternary ammonium ion catalysts. Catalyst descriptors including ammonium ion accessibility, interfacial adsorption affinity, and partition coefficient were found to correlate meaningfully with catalyst activity. The physical nature of the descriptors was rationalized through differing contributions of the interfacial and extraction mechanisms to the reaction under study. The variation in the observed enantioselectivity was rationalized employing a comparative molecular field analysis (CoMFA) using both the steric and electrostatic fields of the catalysts. A qualitative analysis of the developed model reveals preferred regions for catalyst binding to afford both configurations of the alkylated product.

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Transport in QSAR III

Cited by 5 publications

References 18 publications

Molecular Properties and Pharmacokinetic Behavior of Cetirizine, a Zwitterionic H₁-Receptor Antagonist

Molecular Properties and Pharmacokinetic Behavior of Cetirizine, a Zwitterionic H₁-Receptor Antagonist

Modeling Kinetics of Subcellular Disposition of Chemicals

A Systematic Investigation of Quaternary Ammonium Ions as Asymmetric Phase-Transfer Catalysts. Application of Quantitative Structure Activity/Selectivity Relationships

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Transport in QSAR III

Cited by 5 publications

References 18 publications

Molecular Properties and Pharmacokinetic Behavior of Cetirizine, a Zwitterionic H1-Receptor Antagonist

Molecular Properties and Pharmacokinetic Behavior of Cetirizine, a Zwitterionic H1-Receptor Antagonist

Modeling Kinetics of Subcellular Disposition of Chemicals

A Systematic Investigation of Quaternary Ammonium Ions as Asymmetric Phase-Transfer Catalysts. Application of Quantitative Structure Activity/Selectivity Relationships

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Product

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Molecular Properties and Pharmacokinetic Behavior of Cetirizine, a Zwitterionic H₁-Receptor Antagonist

Molecular Properties and Pharmacokinetic Behavior of Cetirizine, a Zwitterionic H₁-Receptor Antagonist