- Identification and optimization of soluble epoxide hydrolase inhibitors with dual potency towards fatty acid amide hydrolase
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Multi-target inhibitors have become increasing popular as a means to leverage the advantages of poly-pharmacology while simplifying drug delivery. Here, we describe dual inhibitors for soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH), two targets known to synergize when treating inflammatory and neuropathic pain. The structure activity relationship (SAR) study described herein initially started with t-TUCB (trans-4-[4-(3-trifluoromethoxyphenyl-l-ureido)-cyclohexyloxy]-benzoic acid), a potent sEH inhibitor that was previously shown to weakly inhibit FAAH. Inhibitors with a 6-fold increase of FAAH potency while maintaining high sEH potency were developed by optimization. Interestingly, compared to most FAAH inhibitors that inhibit through time-dependent covalent modification, t-TUCB and related compounds appear to inhibit FAAH through a time-independent, competitive mechanism. These inhibitors are selective for FAAH over other serine hydrolases. In addition, FAAH inhibition by t-TUCB appears to be higher in human FAAH over other species; however, the new dual sEH/FAAH inhibitors have improved cross-species potency. These dual inhibitors may be useful for future studies in understanding the therapeutic application of dual sEH/FAAH inhibition.
- Kodani, Sean D.,Bhakta, Saavan,Hwang, Sung Hee,Pakhomova, Svetlana,Newcomer, Marcia E.,Morisseau, Christophe,Hammock, Bruce D.
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supporting information
p. 762 - 768
(2018/01/27)
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- INHIBITORS FOR SOLUBLE EPOXIDE HYDROLASE (SEH) AND FATTY ACID AMIDE HYDROLASE (FAAH)
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The present invention provides compounds that are dual inhibitors of soluble epoxide hydrolase and fatty acid amide hydrolase. The present invention also provides methods of using the compounds to inhibit soluble epoxide hydrolase and fatty acid amide hydrolase, and to treat cancer.
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Paragraph 0143
(2017/10/11)
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- Tankyrase inhibitor
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The invention belongs to the technical field of medicines and particularly relates to a tankyrase inhibitor represented by a general formula (I) shown in the description and pharmaceutically acceptable salts, esters, solvates or stereoisomers thereof, wherein R1, R2, R3, m, n, Z, L, Q, A, X1, X2 and Y are as defined in the description. The invention further relates to a preparation method for the compounds, pharmaceutical preparations and pharmaceutical compositions containing the compounds and application of the compound and the pharmaceutically acceptable salts, esters, solvates or stereoisomers thereof in preparation of drugs for treating and/or preventing tankyrase mediated cancers and related diseases.
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- NOVEL COMPOUNDS AS HISTAMINE H3 RECEPTOR LIGANDS
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The present invention relates to novel compounds of formula (I), and their pharmaceutically acceptable salts and compositions containing them. The present invention also relates to a process for the preparation of above said novel compounds, and their pha
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- NOVEL COMPOUNDS AS HISTAMINE H3 RECEPTOR LIGANDS
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The present invention relates to novel compounds of formula (I), and their pharmaceutically acceptable salts and compositions containing them. The present invention also relates to a process for the preparation of above said novel compounds, and their pha
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- DRUG COMBINATIONS CONTAINING PDE4 INHIBITORS AND NSAIDS
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The present invention relates to new drug combinations which contain in addition to one or more PDE4-inhibitors at least one NSAID (=non-steroidal anti-inflammatory drug) (2), processes for preparing them and their use in treating in particular respiratory complaints such as for example COPD, chronic sinusitis and asthma. The invention particularly relates to those drug combinations which contain, in addition to one or more, preferably one PDE4 inhibitor of general formula 1 wherein X is SO or SO2, but preferably SO, and wherein R1, R2, R3 and R4 have the meanings given in claim 1, at least one NSAID (2), the preparation thereof and the use thereof for the treatment of respiratory complaints.
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- 4-Phenoxypiperidines: Potent, conformationally restricted, non-imidazole histamine H3 antagonists
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Two new series of 4-(1-alkyl-piperidin-4-yloxy)-benzonitriles and 4-(1-isopropyl-piperidin-4-yloxy)-benzylamines have been prepared. In vitro activity was determined at the recombinant human H3 receptor and several members of these new series were found to be potent H3 antagonists. The present compounds contain a 4-phenoxypiperidine core, which behaves as a conformationally restricted version of the 3-amino-1-propanol moiety common to the many previously described non-imidazole histamine H 3 ligands. One selected member of the new series, 4-[4-(1-isopropyl-piperidin-4-yloxy)-benzyl]-morpholine (13g), was found to be a potent, highly selective H3 receptor antagonist with in vivo efficacy in a rat EEG model of wakefulness at doses as low as 1 mg/kg sc.
- Dvorak, Curt A.,Apodaca, Richard,Barbier, Ann J.,Berridge, Craig W.,Wilson, Sandy J.,Boggs, Jamin D.,Xiao, Wei,Lovenberg, Timothy W.,Carruthers, Nicholas I.
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p. 2229 - 2238
(2007/10/03)
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