- 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.
- 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.
-
-
Read Online
- Heterocyclic Compound
-
The present invention provide a compound having an orexin receptor antagonistic activity, which is expected to be useful as medicaments such as agents for the prophylaxis or treatment of sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease and the like. The present invention relates to a compound represented by the formula (I): wherein each symbol is as defined in the specification, or a salt thereof.
- -
-
Paragraph 1838; 1841; 1842
(2018/06/15)
-
- DISUBSTITUTED OCTAHY-DROPYRROLO [3,4-C] PYRROLES AS OREXIN RECEPTOR MODULATORS
-
Disubstituted octahydropyrrolo[3,4-c]pyrrole compounds are described, which are useful as orexin receptor modulators. Such compounds may be useful in pharmaceutical compositions and methods for the treatment of diseased states, disorders, and conditions mediated by orexin activity, such as insomnia.
- -
-
Page/Page column 84
(2012/11/07)
-
- FUSED HETEROCYCLIC COMPOUNDS AS OREXIN RECEPTOR MODULATORS
-
Disubstituted 3,8-diaza-bicyclo[4.2.0]octane and 3,6-diazabicyclo [3.2.0]heptane compounds are described, which are useful as orexin receptor modulators. Such compounds may be useful in pharmaceutical compositions and methods for the treatment of diseased states, disorders, and conditions mediated by orexin activity, such as insomnia.
- -
-
Page/Page column 90
(2011/05/06)
-
- FUSED HETEROCYCLIC COMPOUNDS AS OREXIN RECEPTOR MODULATORS
-
Certain disubstituted 3,8-diaza-bicyclo[4.2.0]octane and 3,6-diazabicyclo [3.2.0]heptane are described, which are useful as orexin inhibitors. Such compounds may be useful in pharmaceutical compositions and methods for the treatment of diseased states, disorders, and conditions mediated by orexin activity, such as insomnia.
- -
-
Page/Page column 62
(2011/05/06)
-
- THIOPHENYL-SUBSTITUTED 2-IMINO-3-METHYL PYRROLO PYRIMIDINONE COMPOUNDS AS BACE-1 INHIBITORS, COMPOSITIONS, AND THEIR USE
-
In its many embodiments, the present invention provides provides certain thiophenyl-substituted 2-imino-3-methyl pyrrolo pyrimidone compounds, including compounds (or tautomers or a pharmaceutically acceptable salts thereof) having the structural Formula (III): wherein R2, R3, R4, R5, R6, R7, R8, and R9 are each selected independently and as defined herein. Pharmaceutical compositions comprising one or more such compounds, and methods for their preparation and use in treating pathologies associated with amyloid beta (Aβ) protein, including Alzheimer's Disease, are also disclosed.
- -
-
Page/Page column 89
(2009/12/05)
-