Metabolically Stable tert-Butyl Replacement

被引：108

作者：

Barnes-Seeman, David ^{[1
]}

Jain, Monish ^{[2
]}

Bell, Leslie ^{[2
]}

Ferreira, Suzie ^{[2
]}

Cohen, Scott ^{[1
]}

Chen, Xiao-Hui ^{[2
]}

Amin, Jakal ^{[2
]}

Snodgrass, Brad ^{[2
]}

Hatsis, Panos ^{[2
]}

机构：

[1] Novartis Inst Biomed Res, Dept Global Discovery Chem, Cambridge, MA 02139 USA

[2] Novartis Inst Biomed Res, Dept Metab & Pharmacokinet, Cambridge, MA 02139 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2013年 / 4卷 / 06期

关键词：

Metabolic stability; metabolism; clearance; tertiary butyl; tert-butyl; t-butyl; DISCOVERY; OXETANES; CYTOCHROME-P450;

D O I：

10.1021/ml400045j

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：514 / 516

页数：3

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