67748-61-2Relevant articles and documents
Structure-based discovery of 1H-indole-2-carboxamide derivatives as potent ASK1 inhibitors for potential treatment of ulcerative colitis
Hou, Shaohua,Yang, Xiping,Tong, Yu,Yang, Yuejing,Chen, Quanwei,Wan, Boheng,Wei, Ran,Wang, Yuchen,Zhang, Yanmin,Kong, Bo,Huang, Jianhang,Chen, Yadong,Lu, Tao,Hu, Qinghua,Du, Ding
, (2020/12/29)
Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase (MAPK) family, is implicated in many human diseases. Here, we describe the structural optimization of hit compound 7 and conduct further structure-activity relationship (SAR) studies that result in the development of compound 19 with a novel indole-2-carboxamide hinge scaffold. Compound 19 displays potent anti-ASK1 kinase activity and stronger inhibitory effect on ASK1 in AP1-HEK293 cells than previously described ASK1 inhibitor GS-4997. Besides improved in vitro activity, compound 19 also exhibits an appropriate in vivo PK profile. In a dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis (UC), compound 19 shows significant anti-UC efficacy and markedly attenuates DSS-induced body weight loss, colonic shortening, elevation in disease activity index (DAI) and inflammatory cell infiltration in colon tissues. Mechanistically, compound 19 represses the phosphorylation of ASK1-p38/JNK signaling pathways and suppresses the overexpression of inflammatory cytokines. Together, these findings suggest that ASK1 inhibitors can potentially be used as a therapeutic strategy for UC.
Novel tetrahydropyrido[1,2-a]isoindolone derivatives (valmerins): Potent cyclin-dependent kinase/glycogen synthase kinase 3 inhibitors with antiproliferative activities and antitumor effects in human tumor xenografts
Boulahjar, Rajaa,Ouach, Aziz,Matteo, Chiurato,Bourg, Stephane,Ravache, Myriam,Guével, Rémy Le,Marionneau, Séverine,Oullier, Thibauld,Lozach, Olivier,Meijer, Laurent,Guguen-Guillouzo, Christiane,Lazar, Sa?d,Akssira, Mohamed,Troin, Yves,Guillaumet, Gérald,Routier, Sylvain
, p. 9589 - 9606 (2013/01/16)
The development of CDK and GSK3 inhibitors has been regarded as a potential therapeutic approach, and a substantial number of diverse structures have been reported to inhibit CDKs and GSK-3β in recent years. Only a few molecules have gone through or are currently undergoing clinical trials as CDK and GSK inhibitors. In this paper, we prepared valmerins, a new family containing the tetrahydropyrido[1,2-a]isoindone core. The fused heterocycle was prepared with a straightforward synthesis that was functionalized by a (het)arylurea. Twelve valmerins inhibited the CDK5 and GSK3 with an IC50 100 nM. A semiquantitative kinase scoring was realized, and a cellular screening was done. At the end of our study, we investigated the in vivo potency of one valmerin. Mice exhibited good tolerance to our lead, which proved its efficacy and clearly blocked tumor growth. Valmerins appear also as good candidates for further development as anticancer agents.
BENZIMIDAZOLE OR INDOLE AMIDES AS INHIBITORS OF PIN1
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Page/Page column 30-31, (2010/11/08)
The invention relates to compounds of the formula (1) and to pharmaceutically acceptable salts and solvates thereof, wherein the variables are defined herein. The invention also relates to methods of treating abnormal cell growth in mammals by administering the compounds of formula (1) and to pharmaceutical compositions for treating such disorders that contain the compounds of formula (1). The invention also relates to methods of preparing the compounds of formula (1).
