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

By identifying every pair of molecules that differ only by a particular, well-defined, structural transformation in a database of measured properties and computing the corresponding change in property, we obtain an overview of the effect that structural change has upon the property and set an expect...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2006-11, Vol.49 (23), p.6672-6682
Main Authors: Leach, Andrew G, Jones, Huw D, Cosgrove, David A, Kenny, Peter W, Ruston, Linette, MacFaul, Philip, Wood, J. Matthew, Colclough, Nicola, Law, Brian
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Biological and medical sciences
Blood Proteins - metabolism
Databases, Factual
Drug Design
Hydrogen Bonding
Medical sciences
Methylation
Miscellaneous
Models, Molecular
Molecular Structure
Pharmaceutical Preparations - administration & dosage
Pharmaceutical Preparations - chemistry
Pharmaceutical Preparations - metabolism
Pharmacokinetics
Pharmacology. Drug treatments
Piperazines - chemistry
Piperazines - metabolism
Piperidines - chemistry
Piperidines - metabolism
Protein Binding
Rats
Software
Solubility
Structure-Activity Relationship
Water
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Summary:By identifying every pair of molecules that differ only by a particular, well-defined, structural transformation in a database of measured properties and computing the corresponding change in property, we obtain an overview of the effect that structural change has upon the property and set an expectation for what will happen when that transformation is applied elsewhere. The mean change indicates the expected magnitude of the change in the property and the number of cases in which the property increases give the probability that the structural transformation will cause the property to increase. Outliers indicate potential ways of avoiding the general trend. Comparing to changes in lipophilicity highlights structural transformations that have unusual effects, some of which can be explained by conformational changes. In this paper, we focus upon the effects on aqueous solubility, plasma protein binding and oral exposure of adding substituents to aromatic rings and methylating heteroatoms.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0605233