- Discovery and optimization of a series of small-molecule allosteric inhibitors of MALT1 protease
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We describe a series of potent and highly selective small-molecule MALT1 inhibitors, optimized from a High-Throughput Screening hit. Advanced analogues such as compound 40 show high potency (IC50: 0.01 μM) in a biochemical assay measuring MALT1 enzymatic activity, as well as in cellular assays: Jurkat T cell activation (0.05 μM) and IL6/10 secretion (IC50: 0.10/0.06 μM) in the TMD8 B-cell lymphoma line. Compound 40 also inhibited cleavage of the MALT1 substrate RelB (IC50: 0.10 μM). Mechanistic enzymology results suggest that these compounds bind to the known allosteric site of the protease.
- Lu, Tianbao,Connolly, Peter J.,Philippar, Ulrike,Sun, Weimei,Cummings, Maxwell D.,Barbay, Kent,Gys, Luc,Van Nuffel, Luc,Austin, Nigel,Bekkers, Mariette,Shen, Fang,Cai, Ann,Attar, Ricardo,Meerpoel, Lieven,Edwards, James
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- AMIDE DERIVATIVE
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An amide derivative represented by the formula (I) wherein A is a cycloalkyl group, an aryl group or a heteroaryl group, X is a nitrogen atom or CR17, Y is NRa, -(CRbRb')m- and the like, m is 0-4, and R1-R17 may be the same or different and each is a hydrogen atom, a halogen atom, a cyano group, a nitro group, a carboxyl group, a formyl group, a hydroxyl group, an ammonium group, an alkyl group optionally having a substituent(s), ZR18 and the like, Z is -O-, -S(O)p-, -S(O)pO-, -NH-, -NR19- and the like, or R1 and R2 may in combination form a ring, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof is applied to pharmaceutical use such as anti-inflammatory and analgesic action and the like.
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Page/Page column 16
(2008/06/13)
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- PIPERIDINE/CYCLOHEXANE CARBOXAMIDE DERIVATIVES FOR USE AS VANILLOID RECEPTOR MODULATORS
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Certain compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, P, P', X, m and n are as defined in the specification, a process for preparing such compounds, a pharmaceutical composition c
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Page/Page column 13
(2010/02/10)
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- Identification and biological evaluation of 4-(3-trifluoromethylpyridin-2- yl)piperazine-1-carboxylic acid (5-trifluoromethylpyridin-2-yl)amide, a high affinity TRPV1 (VR1) vanilloid receptor antagonist
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High throughput screening using the recombinant human TRPV1 receptor was used to identify a series of pyridinylpiperazine ureas (3) as TRPV1 vanilloid receptor ligands. Exploration of the structure-activity relationships by parallel synthesis identified t
- Swanson, Devin M.,Dubin, Adrienne E.,Shah, Chandra,Nasser, Nadia,Chang, Leon,Dax, Scott L.,Jetter, Michele,Breitenbucher, J. Guy,Liu, Changlu,Mazur, Curt,Lord, Brian,Gonzales, Lisa,Hoey, Kenway,Rizzolio, Michele,Bogenstaetter, Michael,Codd, Ellen E.,Lee, Doo H.,Zhang, Sui-Po,Chaplan, Sandra R.,Carruthers, Nicholas I.
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p. 1857 - 1872
(2007/10/03)
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