title: Matched molecular pairs as a guide in the optimization of pharmaceutical properties; a study of aqueous solubility, plasma protein binding and oral exposure.
abstract: 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.
authors.affiliation: AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield SK10 4TG, UK. andrew.leach@astrazeneca.com
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Leach
authors.forename: Huw D
authors.initials: HD
authors.lastname: Jones
authors.forename: David A
authors.initials: DA
authors.lastname: Cosgrove
authors.forename: Peter W
authors.initials: PW
authors.lastname: Kenny
authors.forename: Linette
authors.initials: L
authors.lastname: Ruston
authors.forename: Philip
authors.initials: P
authors.lastname: MacFaul
authors.forename: J Matthew
authors.initials: JM
authors.lastname: Wood
authors.forename: Nicola
authors.initials: N
authors.lastname: Colclough
authors.forename: Brian
authors.initials: B
authors.lastname: Law
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D016208:Databases, Factual; D015195:Drug Design; D006860:Hydrogen Bonding; D008745:Methylation; D008958:Models, Molecular; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism*; D010599:Pharmacokinetics; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D012984:Software; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water
chemical_list: D001798:Blood Proteins; D004364:Pharmaceutical Preparations; D010879:Piperazines; D010880:Piperidines; D014867:Water