959748-99-3Relevant academic research and scientific papers
Discovery of a class of highly potent Janus Kinase 1/2 (JAK1/2) inhibitors demonstrating effective cell-based blockade of IL-13 signaling
Zak, Mark,Hanan, Emily J.,Lupardus, Patrick,Brown, David G.,Robinson, Colin,Siu, Michael,Lyssikatos, Joseph P.,Romero, F. Anthony,Zhao, Guiling,Kellar, Terry,Mendonca, Rohan,Ray, Nicholas C.,Goodacre, Simon C.,Crackett, Peter H.,McLean, Neville,Hurley, Christopher A.,Yuen, Po-wai,Cheng, Yun-Xing,Liu, Xiongcai,Liimatta, Marya,Kohli, Pawan Bir,Nonomiya, Jim,Salmon, Gary,Buckley, Gerry,Lloyd, Julia,Gibbons, Paul,Ghilardi, Nico,Kenny, Jane R.,Johnson, Adam
supporting information, p. 1522 - 1531 (2019/04/25)
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).
NOVEL COMPOUNDS AS CANNABINOID RECEPTOR LIGANDS AND USES THEREOF
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Page/Page column 138-139, (2009/06/27)
The present invention relates to compounds of formula (I), or pharmaceutical salts, prodrugs, salts of prodrugs, or combinations thereof, formula (I). wherein R1, R2, R3, R4, and L1 are defined in the specfication, compositions comprising such compounds, and methods of treating conditions and disorders using such compounds and compositions. The present invention also relates to compounds of formula (II), or pharmaceutical salts, prodrugs, salts of prodrugs, or combinations thereof, formula (II). wherein R1a, R2a, Rx, and n are as defined in the specification, compositions comprising such compounds, and methods of treating conditions and disorders using such compounds and compositions.
