Abstract
The lymphocyte-specific kinase (Lck), a member of the Src family of cytoplasmic tyrosine kinases, is expressed in T cells and natural killer (NK) cells. Genetic evidence, including knockout mice and human mutations, demonstrates that Lck kinase activity is critical for normal T cell development, activation, and signaling. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disease. With the aid of X-ray structure-based analysis, aminopyrimidine amides 2 and 3 were designed from aminoquinazolines 1, which had previously been demonstrated to exhibit potent inhibition of Lck and T cell proliferation. In this report, we describe the synthesis and structure-activity relationships of a series of novel aminopyrimidine amides 3 possessing improved cellular potency and selectivity profiles relative to their aminoquinazoline predecessors 1. Orally bioavailable compound 13b inhibited the anti-CD3-induced production of interleukin-2 (IL-2) in mice in a dose-dependent manner (ED 50 = 9.4 mg/kg).
MeSH terms
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Administration, Oral
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Amides / chemical synthesis
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Amides / chemistry
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Amides / pharmacology*
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Animals
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Cell Proliferation / drug effects
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Crystallography, X-Ray
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Dose-Response Relationship, Drug
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Drug Design
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Enzyme Activation / drug effects
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Female
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Humans
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Interleukin-2 / antagonists & inhibitors
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Interleukin-2 / metabolism
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Killer Cells, Natural / drug effects
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Killer Cells, Natural / metabolism
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Lipopolysaccharides / pharmacology
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / antagonists & inhibitors*
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Models, Molecular
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Molecular Structure
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry
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Pyrimidines / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Stereoisomerism
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Structure-Activity Relationship
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T-Lymphocytes / drug effects*
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T-Lymphocytes / metabolism
Substances
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Amides
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Interleukin-2
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Lipopolysaccharides
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Protein Kinase Inhibitors
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Pyrimidines
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck)