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

• Published in: Journal of medicinal chemistry Vol. 61; no. 23; pp. 10700 - 10708
• Main Authors: Mandal, Mihirbaran, Mitra, Kaushik, Grotz, Diane, Lin, Xinjie, Palamanda, Jairam, Kumari, Pramila, Buevich, Alexei, Caldwell, John P, Chen, Xia, Cox, Kathleen, Favreau, Leonard, Hyde, Lynn, Kennedy, Matthew E, Kuvelkar, Reshma, Liu, Xiaoxiang, Mazzola, Robert D, Parker, Eric, Rindgen, Diane, Sherer, Edward, Wang, Hongwu, Zhu, Zhaoning, Stamford, Andrew W, Cumming, Jared N
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.12.2018; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; MECHANISM-BASED INACTIVATION; METABOLISM; TRIMETHOPRIM; A-BETA; FLUORINE; IDENTIFICATION; DISCOVERY; STRUCTURE-BASED DESIGN; BACE
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b01326

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.