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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.

SUBMITTER: Barnes-Seeman D

PROVIDER: S-EPMC4027455 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Metabolically Stable tert-Butyl Replacement.

Barnes-Seeman David D Jain Monish M Bell Leslie L Ferreira Suzie S Cohen Scott S Chen Xiao-Hui XH Amin Jakal J Snodgrass Brad B Hatsis Panos P

ACS medicinal chemistry letters 20130422 6

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 t ...[more]

PMID: 24900702

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