title: Strategies to improve in vivo toxicology outcomes for basic candidate drug molecules.
abstract: A valid PLS-DA model to predict attrition in pre-clinical toxicology for basic oral candidate drugs was built. A combination of aromatic/aliphatic balance, flatness, charge distribution and size descriptors helped predict the successful progression of compounds through a wide range of toxicity testing. Eighty percent of an independent test set of marketed post-2000 basic drugs could be successfully classified using the model, indicating useful forward predictivity. The themes within this work provide additional guidance for medicinal design chemists and complement other literature property guidelines.
authors.affiliation: AstraZeneca R&D, Medicinal Chemistry, Charnwood, Loughborough, Leicestershire LE11 5RH, UK. Tim.Luker@astrazeneca.com
authors.forename: Tim
authors.initials: T
authors.lastname: Luker
authors.forename: Lilian
authors.initials: L
authors.lastname: Alcaraz
authors.forename: Kamaldeep K
authors.initials: KK
authors.lastname: Chohan
authors.forename: Niklas
authors.initials: N
authors.lastname: Blomberg
authors.forename: Dearg S
authors.initials: DS
authors.lastname: Brown
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Butlin
authors.forename: Thomas
authors.initials: T
authors.lastname: Elebring
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Griffin
authors.forename: Simon
authors.initials: S
authors.lastname: Guile
authors.forename: Stephen
authors.initials: S
authors.lastname: St-Gallay
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Swahn
authors.forename: Steve
authors.initials: S
authors.lastname: Swallow
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Waring
authors.forename: Mark C
authors.initials: MC
authors.lastname: Wenlock
authors.forename: Paul D
authors.initials: PD
authors.lastname: Leeson
mesh_terms: D000818:Animals; D016002:Discriminant Analysis; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004345:Drug Industry / Q000379:methods*; D006801:Humans; D015233:Models, Statistical; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D004364:Pharmaceutical Preparations