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.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Pyrimidines/chemical synthesis , Thiazoles/chemical synthesis , src-Family Kinases/antagonists & inhibitors , Administration, Oral , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arthritis, Experimental/drug therapy , Cell Proliferation/drug effects , Chronic Disease , Dasatinib , Female , Humans , In Vitro Techniques , Inflammation/blood , Inflammation/chemically induced , Interleukin-2/antagonists & inhibitors , Lipopolysaccharides , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Models, Molecular , Protein Binding , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Rats, Inbred Lew , Structure-Activity Relationship , T-Lymphocytes/cytology , T-Lymphocytes/drug effects , Thiazoles/chemistry , Thiazoles/pharmacology , Tumor Necrosis Factor-alpha/metabolismABSTRACT
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.
Subject(s)
Amides/pharmacology , Anti-Inflammatory Agents/pharmacology , Enzyme Inhibitors/pharmacology , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Thiazoles/pharmacology , src-Family Kinases/antagonists & inhibitors , Administration, Oral , Amides/chemical synthesis , Amides/pharmacokinetics , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacokinetics , Arthritis, Experimental/therapy , Disease Models, Animal , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Male , Models, Molecular , Molecular Structure , Rats , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacokineticsABSTRACT
A novel series of 2-amino-5-carboxamidothiazoles were identified as inhibitors of Lck. Structure-activity studies demonstrate the structural requirements for potent Lck activity. Cyclopropylamide 11d is a potent Lck inhibitor having sub-micromolar activity in a PBL proliferation assay.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Amino Acid Sequence , Binding Sites , Drug Design , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/chemistry , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
We have identified a novel series of 1,5-imidazoquinoxalines as inhibitors of Lck with excellent potency (IC50s<5 nM) as well as good cellular activity against T-cell proliferation (IC50s<1 microM). Structure-activity studies demonstrate the requirement for the core heterocycle in addition to an optimal 2,6-disubstituted aniline group.