Overcoming Time-Dependent Inhibition (TDI) of Cytochrome P450 3A4 (CYP3A4) Resulting from Bioactivation of a Fluoropyrimidine Moiety

Herein we describe structure–activity relationship (SAR) and metabolite identification (Met-ID) studies that provided insight into the origin of time-dependent inhibition (TDI) of cytochrome P450 3A4 (CYP3A4) by compound 1. Collectively, these efforts revealed that bioactivation of the fluoropyrimidine moiety of 1 led to reactive metabolite formation via oxidative defluorination and was responsible for the observed TDI. We discovered that substitution at both the 4- and 6-positions of the 5-fluoropyrimidine of 1 was necessary to ameliorate this TDI as exemplified by compound 19.本研究报道了构效关系（structure–activity relationship, SAR）与代谢物鉴定（metabolite identification, Met-ID）研究，阐明了化合物1对细胞色素P450 3A4（cytochrome P450 3A4, CYP3A4）产生时间依赖性抑制（time-dependent inhibition, TDI）的根源。上述研究共同揭示：化合物1的氟嘧啶基团经氧化脱氟过程发生生物活化并生成活性代谢物，这正是所观测到的TDI的成因。本研究发现，若要改善该TDI现象，需对化合物1的5-氟嘧啶的4位和6位同时进行取代修饰，如化合物19所示。