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).
Dermatitis, Atopic/genetics , Interleukin-13/metabolism , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Humans , Signal Transduction
We report the optimization of a series of non-steroidal GR antagonists that led to the identification of compound 7. This compound is efficacious when dosed orally in an olanzapine-induced weight gain model in rats.
Benzodiazepines/pharmacology , Drug Discovery , Receptors, Glucocorticoid/antagonists & inhibitors , Thymine/analogs & derivatives , Weight Gain/drug effects , Administration, Oral , Animals , Benzodiazepines/administration & dosage , Benzodiazepines/chemistry , Dose-Response Relationship, Drug , Models, Animal , Molecular Structure , Olanzapine , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Thymine/administration & dosage , Thymine/chemistry , Thymine/pharmacology