Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2006-11, Vol.49 (23), p.6819-6832

Ort / Verlag

Washington, DC: American Chemical Society

Erscheinungsjahr

2006

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 12 m 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 12 m 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 12 m 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.