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.
From: Bristol-Myers Squibb Pharmaceutical Research Institute, Post Office Box 4000, Princeton, New Jersey 08543-4000, USA. jagabandhu.das@bms.com
Journal of medicinal chemistry
- Publish Date: Nov 2006
- ISSN: 0022-2623
- Volume: 49
- Issue: 23
- Pages: 6819-32
- Medium: Print
- Language: English
- Citation (JAMA): Das Jagabandhu, Chen Ping, Norris Derek, et al. 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.. J. Med. Chem. Nov 2006;49:6819-32
Abstract
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 approximately 5 mg/kg) and in reducing TNF levels in an acute murine model of inflammation (90% inhibition in LPS-induced TNFalpha 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.
Mesh Headings (Keywords): Administration, Oral, Animals, Anti-Inflammatory Agents, Non-Steroidal, Arthritis, Experimental, Cell Proliferation, Chronic Disease, Female, Humans, Inflammation, Interleukin-2, Lipopolysaccharides, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Models, Molecular, Protein Binding, Pyrimidines, Rats, Rats, Inbred Lew, Structure-Activity Relationship, T-Lymphocytes, Thiazoles, Tumor Necrosis Factor-alpha, src-Family Kinases
Check for Full Text / PubMed Unique Identifier (PMID): 17154512
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