Journal of Medicinal Chemistry p. 10700 - 10708 (2018)
Update date:2022-08-10
Topics:
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.
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.
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