title: Metabolically Stable tert-Butyl Replacement.
abstract: Susceptibility to metabolism is a common issue with the tert-butyl group on compounds of medicinal interest. We demonstrate an approach of removing all the fully sp(3) C-Hs from a tert-butyl group: replacing some C-Hs with C-Fs and increasing the s-character of the remaining C-Hs. This approach gave a trifluoromethylcyclopropyl group, which increased metabolic stability. Trifluoromethylcyclopropyl-containing analogues had consistently higher metabolic stability in vitro and in vivo compared to their tert-butyl-containing counterparts.
authors.affiliation: Department of Global Discovery Chemistry, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: David
authors.initials: D
authors.lastname: Barnes-Seeman
authors.affiliation: Department of Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Monish
authors.initials: M
authors.lastname: Jain
authors.affiliation: Department of Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Leslie
authors.initials: L
authors.lastname: Bell
authors.affiliation: Department of Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Suzie
authors.initials: S
authors.lastname: Ferreira
authors.affiliation: Department of Global Discovery Chemistry, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Cohen
authors.affiliation: Department of Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Chen
authors.affiliation: Department of Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Jakal
authors.initials: J
authors.lastname: Amin
authors.affiliation: Department of Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Brad
authors.initials: B
authors.lastname: Snodgrass
authors.affiliation: Department of Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Panos
authors.initials: P
authors.lastname: Hatsis
keywords: Metabolic stability; clearance; metabolism; t-butyl; tert-butyl; tertiary butyl