R112 (8) is the first small molecule inhibitor of Syk kinase that has advanced to Phase 2 clinical trials [22,65]. Compound 8 inhibited Syk kinase with Ki = 0.096 mM, selectively inhibited tryptase release from human mast cells induced by anti-IgE cross-linking, histamine from basophils, and dust mite allergen induced histamine release from human basophils with EC50s = 0.353, 0.28 and 0.49 mM, respectively. One advantage of compound 8 was its rapid onset of action since rapidly effective treatment is highly desirable during an allergic attack. Compound 8 also inhibited leukotriene C4 (LTC4), proinflammatory cytokines, including tumor necrosis factor a (TNFa), GM-CSF and IL-8, with EC50s = 0.115, 2.01,1.58 and 1.75 mM, respectively. Compound 8 was advanced to a Phase 2, double-blind, randomized, placebo-controlled, parallel-group seasonal allergic rhinitis trial in a park environment over a period of 2 days at two sites . Patients received 6mg of compound 8 b.i.d via metered spray pump delivery to each nostril. The results from these studies demonstrated that the group receiving 8 experienced a 23% decline in clinical symptoms (stuffy nose, itchy nose, sneezes, cough and headache) as compared to the placebo control group, with overall p value of <0.0005. In order to assess activity with existing therapy, a second 7-day, Phase 2 study was conducted with placebo, beclomet-hasone spray and 8 at similar doses to the first study but with greater separation in dosing intervals. During this study, 8 did not differentiate from placebo control, mainly due to insufficient dose coverage believed to be needed to elicit efficacy. Based on the first study, topical intranasal delivery of a Syk kinase inhibitor to allergic rhinitis patients exhibited significant amelioration of symptoms, which included cough, facial pain, and headache as well as itchy and runny nose, sneezing and nasal congestion .
An orally bioavailable prodrug of 4 is currently in clinical trials for treatment of RA and immune thrombocytopenia purpura [33,34,66]. This compound potently inhibited all Syk-dependent cell-based assays, including Fc receptor signaling in human macrophages, neutrophils, mast cells and B-cell receptor signaling in human B cells. Selectivity was demonstrated by the examination of inhibition of phosphorylation in cells, and with a panel of off-target Syk-independent cell-based assays. Inhibition of Flt3, Jak and Lck, was also observed, which for inflammatory processes might be considered to be favorable . Animal models were conducted that could be directly correlated to IC-mediated inflammatory processes proven to be dependent on activating Fcg receptors [33-35]. Such models included the passive Arthus reaction and passive anticollagen type II antibody-induced arthritis (CAIA) models [33-35]. Based on the compound's biological potency, selectivity, PK characteristics, safety and efficacy in IC animal models, it was tested in a double-blind placebo-controlled ascending single dose randomized study in normal healthy male volunteers . Maximum concentrations were attained in a dose proportional manner up to a dose of 400 mg, and attained in 1.2-1.3 hours post-dosing, with a half-life of approximately 15 hours. During this first-in-human (FIH) study, basophil activation was measured as a biomarker by using heparinized blood from the volunteers. Stimulation ex vivo with anti-IgE and degranulation was measured as CD63 cell-surface upregulation on basophils by flow cytometry. The CD63 cell-surface expression was inhibited in a dose dependent manner, and the extent of the CD63 inhibition was directly correlated to increasing concentrations of the drug for as long as 24 hours post dosing. Basophil activation was reduced by 50% at a concentration of 496 7 42 ng/mL which translated to an EC50 = 1.06 pM . This preliminary data provided some initial confirmation of a PK/PD relationship in humans for this class of molecules .
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