title: Heterocyclic replacements for benzene: Maximising ADME benefits by considering individual ring isomers.
abstract: The impact of replacing a mono-substituted benzene (phenyl) ring with thirty three aromatic and nine aliphatic heterocycles on nine ADME-related screens (solubility, lipophilicity, permeability, protein binding CYP450 inhibition and metabolic clearance) was assessed using matched molecular pair analysis. The results indicate that the influence on the ADME profile can differ significantly depending on the ring identity and importantly on the individual regioisomers that are possible for some rings. This information enables the medicinal chemist to make an informed choice about which rings and regioisomers to employ as mono-substituted benzene replacements, based upon the knowledge of how such replacements are likely to influence ADME-related parameters, for example to target higher solubility whilst avoiding CYP450 liabilities.
authors: TJR-Chem, Via Alberto 34C, 21020 Ranco (VA), Italy. Electronic address: tim.j.ritchie@gmail.com.
authors: Timothy J
authors: TJ
authors: Ritchie
authors: Fibrosis Discovery Performance Unit, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK. Electronic address: simon.jf.macdonald@gsk.com.
authors: Simon J F
authors: SJF
authors: Macdonald
mesh_terms: D000818:Animals; D001554:Benzene / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007536:Isomerism; D010539:Permeability; D012995:Solubility
chemical_list: D006571:Heterocyclic Compounds; D001554:Benzene
keywords: ADME; Benzene; Heteroaliphatic; Heteroaromatic; Regioisomer