302964-07-4Relevant articles and documents
The discovery of (R)-2-(sec-butylamino)-N-(2-methyl-5-(methylcarbamoyl)phenyl) thiazole-5-carboxamide (BMS-640994)-A potent and efficacious p38α MAP kinase inhibitor
Hynes Jr., John,Wu, Hong,Pitt, Sidney,Shen, Ding Ren,Zhang, Rosemary,Schieven, Gary L.,Gillooly, Kathleen M.,Shuster, David J.,Taylor, Tracy L.,Yang, XiaoXia,McIntyre, Kim W.,McKinnon, Murray,Zhang, Hongjian,Marathe, Punit H.,Doweyko, Arthur M.,Kish, Kevin,Kiefer, Susan E.,Sack, John S.,Newitt, John A.,Barrish, Joel C.,Dodd, John,Leftheris, Katerina
, p. 1762 - 1767 (2008/12/20)
A novel structural class of p38α MAP kinase inhibitors has been identified via iterative SAR studies of a focused deck screen hit. Optimization of the lead series generated 6e, BMS-640994, a potent and selective p38α inhibitor that is orally efficacious in rodent models of acute and chronic inflammation.
2-Aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6- [4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-1, 3-thiazole-5-carboxamide (Dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor
Das, Jagabandhu,Chen, Ping,Norris, Derek,Padmanabha, Ramesh,Lin, James,Moquin, Robert V.,Shen, Zhongqi,Cook, Lynda S.,Doweyko, Arthur M.,Pitt, Sidney,Pang, Suhong,Shen, Ding Ren,Fang, Qiong,De Fex, Henry F.,McIntyre, Kim W.,Shuster, David J.,Gillooly, Kathleen M.,Behnia, Kamelia,Schieven, Gary L.,Wityak, John,Barrish, Joel C.
, p. 6819 - 6832 (2007/10/03)
2-Aminothiazole (1) was discovered as a novel Src family kinase inhibitor template through screening of our internal compound collection. Optimization through successive structure-activity relationship iterations identified analogs 2 (Dasatinib, BMS-354825) and 12m as pan-Src inhibitors with nanomolar to subnanomolar potencies in biochemical and cellular assays. Molecular modeling was used to construct a putative binding model for Lck inhibition by this class of compounds. The framework of key hydrogen-bond interactions proposed by this model was in agreement with the subsequent, published crystal structure of 2 bound to structurally similar Abl kinase. The oral efficacy of this class of inhibitors was demonstrated with 12m in inhibiting the proinflammatory cytokine IL-2 ex vivo in mice (ED50 ～ 5 mg/kg) and in reducing TNF levels in an acute murine model of inflammation (90% inhibition in LPS-induced TNFα production when dosed orally at 60 mg/kg, 2 h prior to LPS administration). The oral efficacy of 12m was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally at 0.3 and 3 mg/kg twice daily. Dasatinib (2) is currently in clinical trials for the treatment of chronic myelogenous leukemia.
Discovery of novel 2-(aminoheteroaryl)-thiazole-5-carboxamides as potent and orally active Src-family kinase p56Lck inhibitors
Chen, Ping,Norris, Derek,Das, Jagabandhu,Spergel, Steven H.,Wityak, John,Leith, Leslie,Zhao, Rulin,Chen, Bang-Chi,Pitt, Sidney,Pang, Suhong,Shen, Ding Ren,Zhang, Rosemary,De Fex, Henry F.,Doweyko, Arthur M.,McIntyre, Kim W.,Shuster, David J.,Behnia, Kamelia,Schieven, Gary L.,Barrish, Joel C.
, p. 6061 - 6066 (2007/10/03)
A series of substituted 2-(aminoheteroaryl)-thiazole-5-carboxamide analogs have been synthesized as novel, potent inhibitors of the Src-family kinase p56Lck. Among them, compound 2 displayed superior in vitro potency and excellent in vivo efficacy. A series of substituted 2-(aminoheteroaryl)- thiazole-5-carboxamide analogs have been synthesized as novel, potent inhibitors of the Src-family kinase p56Lck. Among them, compound 2 displayed superior in vitro potency and excellent in vivo efficacy.
Cyclic protein tyrosine kinase inhibitors
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Page 94-95, (2010/02/06)
Novel cyclic compounds and salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds in the treatment of protein tyrosine kinase-associated disorders such as immunologic and oncologic disorders.
