- Identification of SD-0006, a potent diaryl pyrazole inhibitor of p38 MAP kinase
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Starting from an initial HTS screening lead, a novel series of C(5)-substituted diaryl pyrazoles were developed that showed potent inhibition of p38α kinase. Key to this outcome was the switch from a pyridyl to pyrimidine at the C(4)-position leading to analogs that were potent in human whole blood based cell assay as well as in a number of animal efficacy models for rheumatoid arthritis. Ultimately, we identified a clinical candidate from this substrate; SD-0006.
- Walker, John K.,Selness, Shaun R.,Devraj, Rajesh V.,Hepperle, Michael E.,Naing, Win,Shieh, Huey,Kurambail, Ravi,Yang, Syaulan,Flynn, Daniel L.,Benson, Alan G.,Messing, Dean M.,Dice, Tom,Kim, Tina,Lindmark,Monahan, Joseph B.,Portanova, Joseph
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scheme or table
p. 2634 - 2638
(2010/07/13)
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- Synthesis and biological activities of 4-phenyl-5-pyridyl-1,3-thiazole derivatives as selective adenosine A3 antagonists
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To investigate the potency of an adenosine A3 receptor (A 3AR) antagonist as an anti-asthmatic drug, a novel series of 4-phenyl-5-pyridyl-1,3-thiazole derivatives was synthesized and evaluated in human adenosine A1, A
- Miwatashi, Seiji,Arikawa, Yasuyoshi,Matsumoto, Tatsumi,Uga, Keiko,Kanzaki, Naoyuki,Imai, Yumi N.,Ohkawa, Shigenori
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experimental part
p. 1126 - 1137
(2009/09/25)
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- THERAPEUTIC FLUOROETHYL UREAS
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Compounds of the formula or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein A and B are as described herein, are useful for treating conditions afflicting mammals.
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Page/Page column 24
(2008/06/13)
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- Substituted pyrazoles as p38 kinase inhibitors
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A class of pyrazole derivatives is described for use in treating p38 kinase mediated disorders. Compounds of particular interest are defined by Formula (IA), wherein R1, R2, R3 and R4 are as described in the spe
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Page/Page column 134
(2010/02/15)
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- Synthesis and biological activities of 4-phenyl-5-pyridyl-1,3-thiazole derivatives as p38 MAP kinase inhibitors
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A novel series of 4-phenyl-5-pyridyl-1,3-thiazole analogues possessing potent in vitro inhibitory activity against p38 mitogen-activated protein kinase and the release of tumor necrosis factor-α (TNF-α) from human monocytic THP-1 cells stimulated by lipopolysaccharide has been identified. Subsequent structure-activity relationship (SAR) studies and optimization for absorption, distribution, metabolism, and elimination (ADME) profiles led to the identification of compounds 7g and 10b as orally active lead candidates that block the in vivo production of proinflammatory cytokine (TNF-α). In pharmacokinetic studies, compound 10b showed good oral administration in mice and demonstrated significant in vivo anti-inflammatory activity in an anti-collagen monoclonal antibody-induced arthritis mouse model (minimum effective dose (MED)=30 mg/kg). Further elucidation of this class of compounds may provide novel anti-inflammatory agents, such as anti-rheumatoid arthritis drugs.
- Miwatashi, Seiji,Arikawa, Yasuyoshi,Naruo, Ken-Ichi,Igaki, Keiko,Watanabe, Yasumasa,Kimura, Hiroyuki,Kawamoto, Tomohiro,Ohkawa, Shigenori
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p. 410 - 418
(2007/10/03)
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- Novel inhibitor of p38 MAP kinase as an anti-TNF-α drug: Discovery of N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (TAK-715) as a potent and orally active anti-rheumatoid arthritis agent
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The p38 mitogen-activated protein (MAP) kinase has been implicated in the proinflammatory cytokine signal pathway, and its inhibitors are potentially useful for the treatment of chronic inflammatory diseases such as rheumatoid arthritis (RA) and inflammat
- Miwatashi, Seiji,Arikawa, Yasuyoshi,Kotani, Etsuo,Miyamoto, Maki,Naruo, Ken-Ichi,Kimura, Hiroyuki,Tanaka, Toshimasa,Asahi, Satoru,Ohkawa, Shigenori
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p. 5966 - 5979
(2007/10/03)
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- Adenosine A3 receptor antagonists
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A pharmaceutical composition for antagonizing adenosine at adenosine A3receptors which comprises a 1,3-azole compound substituted on the 4- or 5-position, or both, by a pyridyl which may be substituted is provided and can be used as a prophylactic and therapeutic agent for asthma, allergosis, inflammation, and so on.
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- Process for making substituted pyrazoles
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This invention relates to a novel process of preparing selected 5-substituted pyrazoles useful as p38 kinase and COX-2 inhibitors.
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