62908-85-4Relevant academic research and scientific papers
IRAK DEGRADERS AND USES THEREOF
-
, (2021/08/13)
The present invention provides compounds, compositions thereof, and methods of using the same.
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
, 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).
Discovery of an Orally Bioavailable, Brain-Penetrating, in Vivo Active Phosphodiesterase 2A Inhibitor Lead Series for the Treatment of Cognitive Disorders
Mikami, Satoshi,Sasaki, Shigekazu,Asano, Yasutomi,Ujikawa, Osamu,Fukumoto, Shoji,Nakashima, Kosuke,Oki, Hideyuki,Kamiguchi, Naomi,Imada, Haruka,Iwashita, Hiroki,Taniguchi, Takahiko
, p. 7658 - 7676 (2017/10/06)
Herein, we describe the discovery of a potent, selective, brain-penetrating, in vivo active phosphodiesterase (PDE) 2A inhibitor lead series. To identify high-quality leads suitable for optimization and enable validation of the physiological function of PDE2A in vivo, structural modifications of the high-throughput screening hit 18 were performed. Our lead generation efforts revealed three key potency-enhancing functionalities with minimal increases in molecular weight (MW) and no change in topological polar surface area (TPSA). Combining these structural elements led to the identification of 6-methyl-N-((1R)-1-(4-(trifluoromethoxy)phenyl)propyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (38a), a molecule with the desired balance of preclinical properties. Further characterization by cocrystal structure analysis of 38a bound to PDE2A uncovered a unique binding mode and provided insights into its observed potency and PDE selectivity. Compound 38a significantly elevated 3′,5′-cyclic guanosine monophosphate (cGMP) levels in mouse brain following oral administration, thus validating this compound as a useful pharmacological tool and an attractive lead for future optimization.
PYRAZOLO[1,5a]PYRIMIDINE DERIVATIVES AS IRAK4 MODULATORS
-
Page/Page column 67, (2012/02/01)
Compounds of the formula I or II: wherein X, m, Ar, R1 and R2 are as defined herein. The subject compounds are useful for treatment of IRAK-mediated conditions.
