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Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings 1

来自 dx.doi.org

阅读量：

2032

作者：

CA Lipinski，F Lombardo，BW Dominy，PJ Feeney

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摘要：

Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described. In the discovery setting `the rule of 5' predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the molecular weight (MWT) is greater than 500 and the calculated Log P (CLogP) is greater than 5 (or MlogP>4.15). Computational methodology for the rule-based Moriguchi Log P (MLogP) calculation is described. Turbidimetric solubility measurement is described and applied to known drugs. High throughput screening (HTS) leads tend to have higher MWT and Log P and lower turbidimetric solubility than leads in the pre-HTS era. In the development setting, solubility calculations focus on exact value prediction and are difficult because of polymorphism. Recent work on linear free energy relationships and Log P approaches are critically reviewed. Useful predictions are possible in closely related analog series when coupled with experimental thermodynamic solubility measurements.

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关键词：

Rule of 5 Computational alert Poor absorption or permeation MWT MLogP H-Bond donors and acceptors Turbidimetric solubility Thermodynamic solubility Solubility calculation

DOI：

10.1016/j.addr.2012.09.019

被引量：

1.7万

年份：

2001

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来源期刊

Advanced Drug Delivery Reviews
1 March 2001

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2013
被引量：1557

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