- Overcoming Time-Dependent Inhibition (TDI) of Cytochrome P450 3A4 (CYP3A4) Resulting from Bioactivation of a Fluoropyrimidine Moiety
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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.
- 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.
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supporting information
p. 10700 - 10708
(2018/11/27)
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- Discovery of KDM5A inhibitors: Homology modeling, virtual screening and structure-activity relationship analysis
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Herein we report the discovery of a series of new KDM5A inhibitors. A three-dimensional (3D) structure model of KDM5A jumonji domain was firstly established based on homology modeling. Molecular docking-based virtual screening was then performed against c
- Wu, Xiaoai,Fang, Zhen,Yang, Bo,Zhong, Lei,Yang, Qiuyuan,Zhang, Chunhui,Huang, Shenzhen,Xiang, Rong,Suzuki, Takayoshi,Li, Lin-Li,Yang, Sheng-Yong
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supporting information
p. 2284 - 2288
(2016/04/20)
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- Antibacterial Compounds
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The present invention provides a compound of the following formula, salts, racemates, diastereomers, enantiomers, esters, carbamates, phosphates, sulfates, deuterated forms and prodrugs thereof. Also provided is the use of these compounds as antibacterials, compositions comprising them and processes for their manufacture.
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Paragraph 0500; 0501
(2013/10/07)
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- IMIDAZOTRIAZINONE COMPOUNDS
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The present invention provides imidazotriazinone compounds which are inhibitors of phosphodiesterase 9 and pharmaceutically acceptable salt thereof. The present invention further provides processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of PDE9 associated diseases or disorders in mammals, including humans.
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Paragraph 0666; 0667; 0668
(2013/10/08)
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- Facile and regioselective synthesis of novel 2,4-disubstituted-5- fluoropyrimidines as potential kinase inhibitors
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2,4-Disubstituted-5-fluoropyrimidine is a biologically active molecular core seen in various anticancer agents such as 5-fluorouracil (5-FU). As part of a programme aimed at discovering kinase inhibitors, routes to two series of novel compounds (5-fluorop
- Wada, Hiroki,Cheng, Lili,Jiang, Ji,Jiang, Zhigan,Xie, Jun,Hu, Tao,Sanganee, Hitesh,Luker, Tim
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scheme or table
p. 1720 - 1724
(2012/05/04)
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- Theramutein modulators
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This invention relates to agents that are inhibitors or activators of variant forms of endogenous proteins and novel methods of identifying such variants. Of particular interest are inhibitors and activators of endogenous protein variants, encoded by genes which have mutated, which variants often arise or are at least first identified as having arisen following exposure to a chemical agent which is known to be an inhibitor or activator of the corresponding unmutated endogenous protein.
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Page/Page column 168
(2010/02/17)
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- THERAMUTEIN MODULATORS
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This invention relates to agents that are inhibitors or activators of variant forms of endogenous proteins and novel methods of identifying such variants. Of particular interest are inhibitors and activators of endogenous protein variants, encoded by genes which have mutated, which variants often arise or are at least first identified as having arisen following exposure to a chemical agent which is known to be an inhibitor or activator of the corresponding unmutated endogenous protein.
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Page/Page column 199
(2008/12/07)
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- SYNTHESIS AND AMINATION OF 2,4-DICHLORO-5-FLUOROPYRIMIDINE
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2,4-Dichloro-5-fluoropyrimidine was prepared by the chlorination of 5-fluorouracil with phosphorus pentachloride in absence of solvent.The reaction of 2,4-dichloro-5-pyrimidine with primary and secondary aliphatic and heteroaromatic amines in an aqueous medium yields 2-chloro-4-RR'-amino-5-fluoropyrimidines, with stereoselective substitution of chlorine in the C4 position.The substances obtained have well-defined fungicidal activity.
- Kovalenko, A. L.,Krutikov, V. I.,Zolotukhina, M. M.,Alekseeva, L. E.
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p. 1122 - 1125
(2007/10/02)
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