- Preclinical Characterization of the FAAH Inhibitor JNJ-42165279
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The pre-clinical characterization of the aryl piperazinyl urea inhibitor of fatty acid amide hydrolase (FAAH) JNJ-42165279 is described. JNJ-42165279 covalently inactivates the FAAH enzyme, but is highly selective with regard to other enzymes, ion channel
- Keith, John M.,Jones, William M.,Tichenor, Mark,Liu, Jing,Seierstad, Mark,Palmer, James A.,Webb, Michael,Karbarz, Mark,Scott, Brian P.,Wilson, Sandy J.,Luo, Lin,Wennerholm, Michelle L.,Chang, Leon,Rizzolio, Michele,Rynberg, Raymond,Chaplan, Sandra R.,Breitenbucher, J. Guy
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Read Online
- Design, synthesis and SAR of antitubercular benzylpiperazine ureas
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Abstract: N-furfuryl piperazine ureas disclosed by scientists at GSK Tres Cantos were chosen as antimycobacterial hits from a phenotypic whole-cell screen. Bioisosteric replacement of the furan ring in the GSK Tres Cantos molecules with a phenyl ring led to molecule (I) with an MIC of 1?μM against Mtb H37Rv, low cellular toxicity (HepG2 IC50 ~ 80?μM), good DMPK properties and specificity for Mtb. With the aim of delineating the SAR associated with (I), fifty-five analogs were synthesized and screened against Mtb. The SAR suggests that the piperazine ring, benzyl urea and piperonyl moieties are essential signatures of this series. Active compounds in this series are metabolically stable, have low cellular toxicity and are valuable leads for optimization. Molecular docking suggests these molecules occupy the Q0 site of QcrB like Q203. Graphic Abstract: Bioisosteric replacement of N-furfuryl piperazine-1-carboxamides yielded molecule (I) a novel lead with satisfactory PD, metabolism, and toxicity profiles.[Figure not available: see fulltext.]
- Satish, Sohal,Chitral, Rohan,Kori, Amitkumar,Sharma, Basantkumar,Puttur, Jayashree,Khan, Afreen A.,Desle, Deepali,Raikuvar, Kavita,Korkegian, Aaron,Martis, Elvis A. F.,Iyer, Krishna R.,Coutinho, Evans C.,Parish, Tanya,Nandan, Santosh
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- Reductive amination by continuous-flow hydrogenation: Direct and scalable synthesis of a benzylpiperazine
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A benzylpiperazine was prepared directly from the corresponding benzaldehyde and piperazine on a continuous-flow hydrogenation apparatus. The synthesis was protecting group free, safe, and environmentally friendly. Large-scale synthesis under flow hydrogenation conditions was also demonstrated. Georg Thieme Verlag Stuttgart · New York.
- Liu, Jing,Fitzgerald, Anne E.,Mani, Neelakandha S.
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p. 2469 - 2473
(2012/09/08)
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- MODULATORS OF FATTY ACID AMIDE HYDROLASE
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4-(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperazine-1 -carboxylic acid (4-chloro-pyridin-3-yl)-amide is described, which is useful as a FAAH modulator. 4-(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperazine-1 -carboxylic acid (4-chloro-pyridin-3-yl)-
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Page/Page column 23-24
(2011/11/30)
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- HETEROARYL-SUBSTITUTED UREA MODULATORS OF FATTY ACID AMIDE HYDROLASE
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Certain heteroaryl-substituted piperidinyl and piperazinyl urea compounds are described, which are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditi
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- PIPERAZINYL AND PIPERIDINYL UREAS AS MODULATORS OF FATTY ACID AMIDE HYDROLASE
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Compounds of formula (I) : wherein, Z is -N-or>CH; R1 is -H or -C1-4alkyl; Ar1 is 2-thiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-primidinyl, 5-pyrimidinyl, or phenyl, each unsubstituted or substituted at a carbon ring member with one or two Ra moieties; Wher each Ra moiety is independently selected from the group consisting of -C1-4alkyl, -C2-4alkenyl, -OH, -OC1-4alkyl, halo, -CF3, -OCF3, -SCF3, -SH, -S(O)0-2C1-4alkyl, -OSO2C1-4alkyl, -CO2C1-4alkyl, -CO2H, -COC1-4alkyl, -N(Rb)Rc, -SO2NRbRc, -NRbSO2Rc, -C(=O)NRbRc, -NO2, and -CN, wherein Rb and Rc are each independently -H or -C1-4alkyl; and Ar2 is defined in the claims are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity. Thus, the compounds may be administered to treat, e.g., anxiety, pain, inflammation, sleep disorders, eating disorders, or movement disorders (such as multiple sclerosis).
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Page/Page column 92
(2008/06/13)
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