Getting physical in drug discovery: a contemporary perspective on solubility and hydrophobicity

被引：187

作者：

Hill, Alan P. ^{[1
]}

Young, Robert J. ^{[2
]}

机构：

[1] GlaxoSmithKline Med Res Ctr, Dept Analyt Chem, Stevenage SG1 2NY, Herts, England

[2] GlaxoSmithKline Med Res Ctr, Dept CSC Med Chem, Stevenage SG1 2NY, Herts, England

来源：

DRUG DISCOVERY TODAY | 2010年 / 15卷 / 15-16期

关键词：

AQUEOUS SOLUBILITY; POOR SOLUBILITY; PERMEABILITY; CHALLENGE;

D O I：

10.1016/j.drudis.2010.05.016

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Suboptimal physical properties have been identified as a particular shortcoming of compounds in contemporary drug discovery, contributing to high attrition levels. An analysis of the relationship between hydrophobicity (calculated and measured) and similar to 100 k measured kinetic solubility values has been undertaken. In line with the General Solubility Equation, estimates of hydrophobicity, particularly ACD c log D(pH7.4), give a useful indication of the likely solubility classification of particular molecules. Taking ACD c log D(pH7.4) values together with the number of aromatic rings in a given molecule provides enhanced prediction. The 'Solubility Forecast Index' (SFI = c log D(pH7.4) #Ar) is proposed as a simple, yet effective, guide to predicting solubility. Moreover, analysis of measured distribution/partition coefficient values highlighted statistically significant shortcomings in the applicability of octanol/water as a model system for hydrophobicity determination with poorly soluble compounds.

引用

页码：648 / 655

页数：8

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