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 fluoropyrimid...
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| Published in | Journal of medicinal chemistry Vol. 61; no. 23; pp. 10700 - 10708 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
WASHINGTON
American Chemical Society
13.12.2018
Amer Chemical Soc |
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| Abstract | 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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| AbstractList | 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. |
| Author | Mazzola, Robert D Rindgen, Diane Lin, Xinjie Parker, Eric Kumari, Pramila Chen, Xia Mandal, Mihirbaran Sherer, Edward Cox, Kathleen Liu, Xiaoxiang Cumming, Jared N Palamanda, Jairam Kuvelkar, Reshma Buevich, Alexei Wang, Hongwu Caldwell, John P Hyde, Lynn Favreau, Leonard Grotz, Diane Stamford, Andrew W Kennedy, Matthew E Mitra, Kaushik Zhu, Zhaoning |
| AuthorAffiliation | Department of Medicinal Chemistry Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism Department of NMR Structure Elucidation Department of Neuroscience Department of Modeling and Informatics |
| AuthorAffiliation_xml | – name: Department of NMR Structure Elucidation – name: Department of Medicinal Chemistry – name: Department of Modeling and Informatics – name: – name: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism – name: Department of Neuroscience |
| Author_xml | – sequence: 1 givenname: Mihirbaran orcidid: 0000-0002-7870-7271 surname: Mandal fullname: Mandal, Mihirbaran email: mihirbaran.mandal@merck.com – sequence: 2 givenname: Kaushik surname: Mitra fullname: Mitra, Kaushik – sequence: 3 givenname: Diane surname: Grotz fullname: Grotz, Diane – sequence: 4 givenname: Xinjie surname: Lin fullname: Lin, Xinjie – sequence: 5 givenname: Jairam surname: Palamanda fullname: Palamanda, Jairam – sequence: 6 givenname: Pramila surname: Kumari fullname: Kumari, Pramila – sequence: 7 givenname: Alexei orcidid: 0000-0002-5968-9151 surname: Buevich fullname: Buevich, Alexei – sequence: 8 givenname: John P surname: Caldwell fullname: Caldwell, John P – sequence: 9 givenname: Xia surname: Chen fullname: Chen, Xia – sequence: 10 givenname: Kathleen surname: Cox fullname: Cox, Kathleen – sequence: 11 givenname: Leonard surname: Favreau fullname: Favreau, Leonard – sequence: 12 givenname: Lynn surname: Hyde fullname: Hyde, Lynn – sequence: 13 givenname: Matthew E surname: Kennedy fullname: Kennedy, Matthew E – sequence: 14 givenname: Reshma surname: Kuvelkar fullname: Kuvelkar, Reshma – sequence: 15 givenname: Xiaoxiang surname: Liu fullname: Liu, Xiaoxiang – sequence: 16 givenname: Robert D surname: Mazzola fullname: Mazzola, Robert D – sequence: 17 givenname: Eric surname: Parker fullname: Parker, Eric – sequence: 18 givenname: Diane surname: Rindgen fullname: Rindgen, Diane – sequence: 19 givenname: Edward orcidid: 0000-0001-8178-9186 surname: Sherer fullname: Sherer, Edward – sequence: 20 givenname: Hongwu surname: Wang fullname: Wang, Hongwu – sequence: 21 givenname: Zhaoning surname: Zhu fullname: Zhu, Zhaoning – sequence: 22 givenname: Andrew W surname: Stamford fullname: Stamford, Andrew W – sequence: 23 givenname: Jared N surname: Cumming fullname: Cumming, Jared N |
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| Keywords | MECHANISM-BASED INACTIVATION METABOLISM TRIMETHOPRIM A-BETA FLUORINE IDENTIFICATION DISCOVERY STRUCTURE-BASED DESIGN BACE |
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| Title | Overcoming Time-Dependent Inhibition (TDI) of Cytochrome P450 3A4 (CYP3A4) Resulting from Bioactivation of a Fluoropyrimidine Moiety |
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