1002309-52-5Relevant articles and documents
Discovery of indazole-pyridinone derivatives as a novel class of potent and selective MNK1/2 kinase inhibitors that protecting against endotoxin-induced septic shock
Dreas, Agnieszka,Kucwaj-Brysz, Katarzyna,Pyziak, Karolina,Kulesza, Urszula,Wincza, Ewelina,Fabritius, Charles-Henry,Michalik, Kinga,Gabor-Worwa, Ewelina,Go?as, Aniela,Milik, Mariusz,Masiejczyk, Magdalena,Majewska, Eliza,Py?niak, Kazimiera,Wójcik-Trechcińska, Urszula,Sandowska-Markiewicz, Zuzanna,Brzózka, Krzysztof,Ostrowski, Jerzy,Rzymski, Tomasz,Mikula, Michal
supporting information, (2020/12/13)
The mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (MNKs 1/2) and their downstream target eIF4E, play a role in oncogenic transformation, progression and metastasis. These results provided rationale for development of first MNKs inhibitors, currently in clinical trials for cancer treatment. Inhibitors of the MNKs/eIF4E pathway are also proposed as treatment strategy for inflammatory conditions. Here we present results of optimization of indazole-pyridinone derived MNK1/2 inhibitors among which compounds 24 and 26, selective and metabolically stable derivatives. Both compounds decreased levels of eIF4E Ser206 phosphorylation (pSer209-eIF4E) in MOLM16 cell line. When administered in mice compounds 24 and 26 significantly improved survival rates of animals in the endotoxin lethal dose challenge model, with concomitant reduction of proinflammatory cytokine levels – TNFα and IL-6 in serum. Identified MNK1/2 inhibitors represent a novel class of immunomodulatory compounds with a potential for the treatment of inflammatory diseases including sepsis.
SUBSTITUTED NITROGEN CONTAINING COMPOUNDS
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Page/Page column 57; 58; 312, (2019/01/05)
Disclosed are compounds of Formula (I): or a salt thereof, Formula (II) wherein R1 is: or; each W is independently NR1b or O; Z is a bond or CHR1d; and R1, R2, Rd, R3a, R3b, L1, B, V, Y, and n are defined herein. Also disclosed are methods of using such compounds as inhibitors of ROMK, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating cardiovascular diseases.
Synthesis and evaluation of thiomannosides, potent and orally active FimH inhibitors
Sattigeri, Jitendra A.,Garg, Malvika,Bhateja, Pragya,Soni, Ajay,Rauf, Abdul Rehman Abdul,Gupta, Mahendrakumar,Deshmukh, Mahesh S.,Jain, Tarun,Alekar, Nidhi,Barman, Tarani Kanta,Jha, Paras,Chaira, Tridib,Bambal, Ramesh B.,Upadhyay, Dilip J.,Nishi, Takahide
, p. 2993 - 2997 (2018/07/21)
FimH is a type I fimbrial lectin located at the tip of type-1 pili of Gram-negative uropathogenic Escherichia coli (UPEC) guiding its ability to adhere and infect urothelial cells. Accordingly, blocking FimH with small molecule inhibitor is considered as a promising new therapeutic alternative to treat urinary tract infections caused by UPEC. Herein, we report that compounds having the S-glycosidic bond (thiomannosides) had improved metabolic stability and plasma exposures when dosed orally. Especially compound 5h showed the potential to inhibit biofilm formation and also to disrupt the preformed biofilm. And compound 5h showed prophylactic effect in UTI model in mice.
