Syk inhibitors

The clinical efficacy of R406/788 (14/15) has heightened interest in Syk inhibition as a therapeutic strategy in RA. There is a clear best-in-class opportunity for Syk inhibitors with improved selectivity and safety profiles (Figure 3). 

Pyrrolopyrazine 22 has an IC50 of 1.7nM against Syk [88] and significantly decreased ankle swelling in prophylactic and therapeutic rat CIA models, and micro-CT scans of ankle joints showed significant inhibition of bone erosion. While 22 is clearly a potent Syk inhibitor, no selectivity or in vitro functional data has been reported. The pyrrolopyrazine scaffold appears in a series of compounds, exemplified by 23, that are substituted in the pyrrole and pyrazine rings [89-92]. These compounds are claimed to inhibit Syk and JAK, but the limited data disclosed suggests that JAK is the dominant activity. 

Atopic dermatitis has been proposed to be the cutaneous manifestation of IgE-mediated hypersensitive reaction to allergenic substances [29]. Conceptually, antagonizing IgE emerges as a logical therapeutic option. Systemic treatment with omalizumab, however, appears to be less efficacious in the skin than in the airway mucosa [23]. It is possible that small molecule Syk inhibitors may offer a more suitable mode to reach and prevent activation of sensitized dermal mast cells and dendritic cells. 

Little information is in the public domain regarding a second Rigel Syk inhibitor R343, believed to be structure (7.10).37 Pfizer licensed the compound from Rigel at the preclinical stage for development as an inhaled drug for the treatment of allergic disorders. To date the compound has completed Phase I... 

Portola Pharmaceuticals Inc, a US based biopharmaceutical company, are currently undertaking a Phase I study with an in-house oral Syk inhibitor PRT-062607 (structure unknown) to evaluate safety, PK and PD in healthy volunteers, ahead of investigating the drug in chronic inflammatory disease indications. Very scant information is known about the compound, except it is claimed to be highly selective for Syk from profiling in a broad panel of in vitro kinase and cellular assays. 

Altman MD, Childers KK, Di Francesco ME, Ellis JM, Fischer C, Grimm J, Haidle AM, Kattar SD, Northrup AB, Otte RD, Petrocchi A, Schell AJ, Zhou H (2012) Aminopyrimidines as syk inhibitors. WO2012/154519... 

Bajpai M (2009) Fostamatinib, a Syk inhibitor prodrug for the treatment of inflammatory diseases. Drugs 12 174-185... 

Researchers at ARIAD Pharmaceuticals described the incorporation of a 3,5-dinitrotyrosine 32 into peptide inhibitors of only double-digit micromolar affinity to the SH2 domains of Syk and Src [136]. 

Spleen Tyrosine Kinase (Syk) Biology, Inhibitors and Therapeutic Applications... 

Syk kinase inhibitors which have progressed to clinical studies 387... 

A number of other small molecule Syk kinase inhibitors have been reported in the literature [61-64], Since there are no reports of detailed evaluation or animal efficacy data, some of these inhibitors may not have advanced further. 

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