title: Rationally designing safer anilines: the challenging case of 4-aminobiphenyls.
abstract: We describe how we have been able to design 4-aminobiphenyls that are nonmutagenic (inactive in the Ames test). No such 4-aminobiphenyls were known to us, but insights provided by quantum mechanical calculations have permitted us to design and synthesize some examples. Importantly, the quantum mechanical calculations could be combined with predictions of other properties of the compounds that contained the 4-aminobiphenyls so that these remained druglike. Having found compounds that are not active, the calculations can provide insight into which factors (electronic and conformational in this case) are important. The calculations provided SAR-like information that was able guide the design of further examples of 4-aminobiphenyls that are not active in the Ames test.
authors.affiliation: AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, SK10 4TG, UK.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Birch
authors.forename: Sam
authors.initials: S
authors.lastname: Groombridge
authors.forename: Robert
authors.initials: R
authors.lastname: Law
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Leach
authors.forename: Christine D
authors.initials: CD
authors.lastname: Mee
authors.forename: Carolin
authors.initials: C
authors.lastname: Schramm
mesh_terms: D000611:Aminobiphenyl Compounds / Q000138:chemical synthesis* / Q000633:toxicity; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000633:toxicity; D004249:DNA Damage; D015195:Drug Design; D008968:Molecular Conformation; D009152:Mutagenicity Tests; D011789:Quantum Theory; D013329:Structure-Activity Relationship
chemical_list: D000611:Aminobiphenyl Compounds; D000814:Aniline Compounds; C006757:4-biphenylamine