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

• Published in: Journal of medicinal chemistry Vol. 49; no. 23; pp. 6819 - 6832
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 16.11.2006; Amer Chemical Soc
• Subjects: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Arthritis, Experimental - drug therapy; Biological and medical sciences; Cell Proliferation - drug effects; Chemistry, Medicinal; Chronic Disease; Dasatinib; Female; Humans; In Vitro Techniques; Inflammation - blood; Inflammation - chemically induced; Interleukin-2 - antagonists & inhibitors; Life Sciences & Biomedicine; Lipopolysaccharides; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - antagonists & inhibitors; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Miscellaneous; Models, Molecular; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protein Binding; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Rats; Rats, Inbred Lew; Science & Technology; src-Family Kinases - antagonists & inhibitors; Structure-Activity Relationship; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; Tumor Necrosis Factor-alpha - metabolism; SIGNAL-TRANSDUCTION; ACTIVATION; LCK; SMALL-MOLECULE INHIBITORS; TYROSINE KINASE; INITIAL SAR; P56(LCK); EXPRESSION; CANCER; MICE LACKING; Rat; Gene product; Thiazole derivatives; Diseases of the osteoarticular system; Arthritis; Signal transduction; Interleukin 2; Structure activity relation; Protein-tyrosine kinase; Tumor necrosis factor α; Dasatinib; Antithyroid agent; Enzyme; Transferases; Rodentia; Cytokine; Organic chlorine compounds; In vitro; In vivo; Vertebrata; Mammalia; Mouse; Animal; C-Onc gene; Carboxamide; Pyrimidine derivatives; Inhibitor; Piperazine derivatives
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm060727j

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.