Bioactivation of cyclopropyl rings by P450: an observation encountered during the optimisation of a series of hepatitis C virus NS5B inhibitors. (2nd December 2018)

• Record Type: Journal Article
• Authors: Zhuo, Xiaoliang; Wang, Ying-Zi; Yeung, Kap-Sun; Zhu, Juliang; Huang, Xiaohua Stella; Parcella, Kyle E.; Eastman, Kyle J.; Kadow, John F.; Meanwell, Nicholas A.; Shu, Yue-Zhong; Johnson, Benjamin M.
• Is Part Of: Xenobiotica. Volume 48:Number 12(2018:Dec.)
• Page Start: 1215
• Page End: 1226
• Publication Date: 2018-12-02
• Subjects: Bioactivation -- cyclopropyl -- glutathione conjugates -- hepatitis C virus inhibitor -- LC/MS -- medicinal chemistry -- metabolism -- NMR -- P450; Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.1080/00498254.2017.1409915
• Languages: English
• ISSNs: 0049-8254

Abstract

Abstract: 1. Due to its unique C–C and C–H bonding properties, conformational preferences and relative hydrophilicity, the cyclopropyl ring has been used as a synthetic building block in drug discovery to modulate potency and drug-like properties. During an effort to discover inhibitors of the hepatitis C virus non-structural protein 5B with improved potency and genotype-coverage profiles, the use of a pyrimidinylcyclopropylbenzamide moiety linked to a C6-substituted benzofuran or azabenzofuran core scaffold was explored in an effort to balance antiviral potency and metabolic stability. 2. In vitro metabolism studies of two compounds from this C6-substituted series revealed an NADPH-dependent bioactivation pathway leading to the formation of multiple glutathione (GSH) conjugates. Analysis of these conjugates by LC-MS and NMR demonstrated that the cyclopropyl group was the site of bioactivation. Based on the putative structures and molecular weights of the cyclopropyl-GSH conjugates, a multi-step mechanism was proposed to explain the formation of these metabolites by P450. This mechanism involves hydrogen atom abstraction to form a cyclopropyl radical, followed by a ring opening rearrangement and reaction with GSH. 3. These findings provided important information to the medicinal chemistry team which responded by replacing the cyclopropyl ring with a gem-dimethyl group. Subsequent compounds bearing this feature were shown to avert the bioactivation pathways in question.