129487-92-9Relevant articles and documents
Discovery of 3-(4-(2-((1 H-Indol-5-yl)amino)-5-fluoropyrimidin-4-yl)-1 H-pyrazol-1-yl)propanenitrile Derivatives as Selective TYK2 Inhibitors for the Treatment of Inflammatory Bowel Disease
Zhang, Chufeng,Qi, Wenyan,Li, Yong,Tang, Minghai,Yang, Tao,Liu, Kongjun,Chen, Yong,Deng, Dexin,Xiang, Mingli,Xiang, Mingli,Chen, Lijuan
, p. 1966 - 1988 (2021)
TYK2 mediates signaling of IL-23, IL-12, and Type I IFN-driven responses that are critical in immune-mediated diseases. Herein, we report the design, synthesis, and structure-activity relationships (SARs) of 3-(4-(2-((1H-indol-5-yl)amino)-5-fluoropyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile derivatives as selective TYK2 inhibitors. Among them, compound 14l exhibited acceptable TYK2 inhibition with an IC50 value of 9 nM, showed satisfactory selectivity characteristics over the other three homologous JAK kinases, and performed good functional potency in the JAK/STAT signaling pathway on lymphocyte lines and human whole blood. In liver microsomal assay studies, the clearance rate and half-life of 14l were 11.4 mL/min/g and 121.6 min, respectively. Furthermore, in a dextran sulfate sodium colitis model, 14l reduced the production of pro-inflammatory cytokines IL-6 and TNF-α and improved the inflammation symptoms of mucosal infiltration, thickening, and edema. Taken together, 14l was a selective TYK2 inhibitor and could be used to treat immune diseases deserving further investigation.
Synthesis and Pharmacological Characterization of Conformationally Restricted Retigabine Analogues as Novel Neuronal Kv7 Channel Activators
Ostacolo, Carmine,Miceli, Francesco,Di Sarno, Veronica,Nappi, Piera,Iraci, Nunzio,Soldovieri, Maria Virginia,Ciaglia, Tania,Ambrosino, Paolo,Vestuto, Vincenzo,Lauritano, Anna,Musella, Simona,Pepe, Giacomo,Basilicata, Manuela Giovanna,Manfra, Michele,Perinelli, Diego Romano,Novellino, Ettore,Bertamino, Alessia,Gomez-Monterrey, Isabel M.,Campiglia, Pietro,Taglialatela, Maurizio
, p. 163 - 185 (2020/01/09)
Kv7 K+ channels represent attractive pharmacological targets for the treatment of different neurological disorders, including epilepsy. In this paper, 42 conformationally restricted analogues of the prototypical Kv7 activator retigabine have been synthesized and tested by electrophysiological patch-clamp experiments as Kv7 agonists. When compared to retigabine (0.93 ± 0.43 μM), the EC50s for Kv7.2 current enhancements by compound 23a (0.08 ± 0.04 μM) were lower, whereas no change in potency was observed for 24a (0.63 ± 0.07 μM). In addition, compared to retigabine, 23a and 24a showed also higher potency in activating heteromeric Kv7.2/Kv7.3 and homomeric Kv7.4 channels. Molecular modeling studies provided new insights into the chemical features required for optimal interaction at the binding site. Stability studies evidenced improved chemical stability of 23a and 24a in comparison with retigabine. Overall, the present results highlight that the N5-alkylamidoindole moiety provides a suitable pharmacophoric scaffold for the design of chemically stable, highly potent and selective Kv7 agonists.
FUSED HETEROCYCLIC COMPOUNDS
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, (2012/01/13)
The present invention provides a compound which has the effect of PDE inhibition, and which is useful as an agent for preventing or treating schizophrenia. The compound is represented by the formula (I): wherein the symbols are defined in the specification.