Spleen Tyrosine Kinase Inhibitors (SYK) as Potential Treatment for Autoimmune and Inflammatory Disorders: Patent Highlight

Ahmed F Abdel-Magid

doi:10.1021/ml300405d

editorial

. 2012 Nov 27;4(1):18–19. doi: 10.1021/ml300405d

Spleen Tyrosine Kinase Inhibitors (SYK) as Potential Treatment for Autoimmune and Inflammatory Disorders

Patent Highlight

Ahmed F Abdel-Magid ^1,^*

PMCID: PMC4027450 PMID: 24900557

Title:	Thiazolopyrimidine Compounds
Patent Application Number:	WO 2012/130780 A1	Publication Date:	4 October 2012
Priority Application:	PCT/CN2011/072211	Priority Date:	28 March 2011
Inventors:	Hermann, J. C.; Lowrie, L. E., Jr.; Lucas, M. C.; Luk, K.-C. T.; Padilla, F.; Wanner, J.; Xie, W.; Zhang, X.
Assignee Company:	F. Hoffmann-La Roche AG; Grenzacherstrasse 124, CH-4070 Basel (CH)
Disease Area:	autoimmune and inflammatory diseases	Biological Target:	SYK (spleen tyrosine kinase)
Summary:	The invention in this patent application relates to the use of novel thiazolopyrimidine derivatives represented by formula I that act as spleen tyrosine kinase (SYK) inhibitors. Such inhibitors may potentially be useful for the treatment of autoimmune and inflammatory diseases.
	Spleen tyrosine kinase (SYK) is a nonreceptor tyrosine kinase that is essential in the transmission of activating signals from the B-cell receptor (BCR). Abnormal SYK activity has been implicated in the development of several cancer, autoimmune, and inflammatory diseases. Therefore, inhibition of this tyrosine kinase might provide a treatment for patients with these diseases.
	SYK is also important in mediating FcεRI mast cell degranulation and eosinophil activation. Mast cells and eosinophils play a key role in controlling several mechanisms associated with allergy and asthma. SYK-deficient mast cells demonstrate defective degranulation, arachidonic acid, and cytokine secretion while SYK-deficient eosinophils show impaired activation in response to FcεR stimulation. SYK has also been implicated in allergic disorders, and its inhibition may provide a useful treatment for asthma and other allergy-induced inflammatory diseases.
	Molecules, such as those described in this patent application, that can inhibit or modulate SYK activity may potentially provide a significant therapy for treatment of autoimmune and inflammatory diseases. The patent application describes (and claims) a list of possible immune disorders that may potentially be treated, including “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.”
Important Compound Classes:
Definitions	B = phenyl, pyridinyl, pyrrolidinyl, or piperidinyl
Key Structures:	The patent application describes a list of 68 specific examples of formula I; the following are six of these compounds:
Biological Assay:	IC₅₀ of spleen tyrosine kinase (SYK) inhibition
Biological Data:	The IC₅₀ values were reported for 68 compounds; the following table contains the data for the above representative examples:
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	2. Ratcliffe A. J.RSC Drug Discovery Ser. 2012, 19 ( Kinase Drug Discovery), 218–243.
	3. Moretto A. F.; Dehnhardt C.; Kaila N.; Papaioannou N.; Thorarensen A.. Recent Pat. Inflammation Allergy Drug Discovery2012, 6 (2), 97–120.