Patent Watch

December 10, 2012

Spleen tyrosine kinase inhibitors may treat autoimmune and inflammatory disorders. J. C. Hermann and co-inventors disclose thiazolopyrimidine derivatives represented by structure 1 (Figure 1) that act as spleen tyrosine kinase (SYK) inhibitors. These inhibitors may be useful for treating autoimmune and inflammatory diseases.

SYK is a nonreceptor tyrosine kinase that is essential for transmitting activating signals from the B-cell receptor. Abnormal SYK activity has been implicated in the development of several cancer, autoimmune, and inflammatory diseases. Inhibitors of this tyrosine kinase might provide treatments for patients with these diseases.

SYK is also important in mediating FcεRI mast-cell degranulation and eosinophil activation. (FcεRI is the high-affinity immunoglobulin E receptor.) Mast cells and eosinophils play a key role in controlling several mechanisms associated with allergy and asthma. SYK-deficient mast cells exhibit defective degranulation, arachidonic acid, and cytokine secretion. SYK-deficient eosinophils show impaired activation in response to FcεRI stimulation. SYK has also been implicated in allergic disorders; inhibiting it may provide a useful treatment for asthma and other allergy-induced inflammatory diseases.

The inventors describe (and claim) molecules that inhibit or modulate SYK activity and may provide a significant therapy for treating autoimmune and inflammatory diseases. Their list of disorders that may potentially be treated includes “lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes, complications from organ transplants, xeno transplantation, diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn’s disease, Alzheimer’s disease, and leukemia.”

The inventors prepared 68 specific examples of structure 1, including the six shown in Figure 2. They biologically assayed the compounds with the IC50 of SYK inhibition metric. The table contains the IC50 results for the representative compounds.

CompoundIC50, μM
20.071
319.90
40.065
50.071
66.152
70.079

(F. Hoffmann-La Roche AG [Basel, Switzerland]. WIPO Publication 2012130780, Oct. 4, 2012; Ahmed F. Abdel-Magid)

This patent was originally reviewed in ACS Medicinal Chemistry Letters.

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