Matched Molecular Pairs as a Guide in the Optimization of Pharmaceutical Properties; a Study of Aqueous Solubility, Plasma Protein Binding and Oral Exposure

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• 作者：Andrew G. Leach ; Huw D. Jones ; David A. Cosgrove ; Peter W. Kenny ; Linette Ruston ; Philip MacFaul ; J. Matthew Wood ; Nicola Colclough ; Brian Law
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：November 16, 2006
• 年：2006
• 卷：49
• 期：23
• 页码：6672 - 6682
• 全文大小：278K
• 年卷期：v.49,no.23(November 16, 2006)
• ISSN：1520-4804

文摘

By identifying every pair of molecules that differ only by a particular, well-defined, structural transformationin a database of measured properties and computing the corresponding change in property, we obtain anoverview of the effect that structural change has upon the property and set an expectation for what willhappen when that transformation is applied elsewhere. The mean change indicates the expected magnitudeof the change in the property and the number of cases in which the property increases give the probabilitythat the structural transformation will cause the property to increase. Outliers indicate potential ways ofavoiding the general trend. Comparing to changes in lipophilicity highlights structural transformations thathave unusual effects, some of which can be explained by conformational changes. In this paper, we focusupon the effects on aqueous solubility, plasma protein binding and oral exposure of adding substituents toaromatic rings and methylating heteroatoms.