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Disruption of interleukin-13 (IL-13) signaling with large molecule antibody therapies has shown promise in diseases of allergic inflammation. Given that IL-13 recruits several members of the Janus Kinase family (JAK1, JAK2, and TYK2) to its receptor complex, JAK inhibition may offer an alternate small molecule approach to disrupting IL-13 signaling. Herein we demonstrate that JAK1 is likely the isoform most important to IL-13 signaling. Structure-based design was then used to improve the JAK1 potency of a series of previously reported JAK2 inhibitors. The ability to impede IL-13 signaling was thereby significantly improved, with the best compounds exhibiting single digit nM IC50's in cell-based assays dependent upon IL-13 signaling. Appropriate substitution was further found to influence inhibition of a key off-target, LRRK2. Finally, the most potent compounds were found to be metabolically labile, which makes them ideal scaffolds for further development as topical agents for IL-13 mediated diseases of the lungs and skin (for example asthma and atopic dermatitis, respectively).

Optimisation of ADS100380, a sub-micromolar HDAC inhibitor identified using a virtual screening approach, led to a series of substituted 5-(1H-pyrazol-3-yl)-thiophene-2-hydroxamic acids (6a-i), that possessed significant HDAC inhibitory activity. Subsequent functionalisation of the pendent phenyl group of compounds 6f and 6g provided analogues 6j-w with further enhanced enzyme and anti-proliferative activity. Compound 6j demonstrated efficacy in a mouse xenograft experiment.

A mild and flexible method for the preparation of bisindolylmaleimides from the corresponding indoles and indole-3-acetimidate esters is described.

Representatives of the title compounds have been prepared from a benzyl-penicillin-derived intermediate.

1,5-Bond ruptures may follow, but do not accompany, 4,7-bond cleavages of penicillanate 1,1-dioxides.

Complexes of imidazoline-2(1,3H)-thione (ImT,L), have been prepared with Co(II) and Zn(II) salts. Stoichiometries of the complexes, ML2X2, for the halides and ML4X2 for the nitrates and perchlorates, have been established by chemical analysis. Thermal analysis has revealed the extent of hydration among the cobalt complexes. The solid complexes have been further characterised by means of magnetic susceptibility data, infrared and visible spectral measurements. The soluble complexes have been studied by means of electrolytic conductance measurements and their visible spectra have also been recorded. Ligand field parameters have been determined and probable structures assigned. The ligand coordinated by means of its exocyclic sulphur atom and one of its ring nitrogen atoms in the solid complexes. For the soluble complexes coordination involves the sulphur atom only.

A procedure has been developed for the high-yield coupling of chiral acetals 1 with allyltrimethylsilane (2, R′=H) as well as with methallyltrimethylsilane (2,R′=ME) to afford the hydroxy ethers 3 in which the new chiral center is formed highly enantioselectively. Homoallylic alcohols 4 of high ee are produced by removal of the chiral auxiliary.