Discovery of piperidinyl aminopyrimidine derivatives as IKK-2 inhibitors

Authors
Kim, SoraJung, Jin KyoLee, Hyo SeonKim, YoungjaeKim, JiyoonChoi, KihangBaek, Du-JongMoon, BongjinOh, Kwang-SeokLee, Byung HoShin, Kye JungPae, Ae NimNam, GhilsooRoh, Eun JooCho, Yong SeoChoo, Hyunah
Issue Date
2011-05-15
Publisher
Pergamon Press Ltd.
Citation
Bioorganic & Medicinal Chemistry Letters, v.21, no.10, pp.3002 - 3006
Abstract
A serine-threonine kinase IKK-2 plays an important role in activation of NF-kappa B through phosphorylation of the inhibitor of NF-kappa B (I kappa B). As NF-kappa B is a major transcription factor that regulates genes responsible for cell proliferation and inflammation, development of selective IKK-2 inhibitors has been an important area of anti-inflammatory and anti-cancer research. In this study, to obtain active and selective IKK-2 inhibitors, various substituents were introduced to a piperidinyl aminopyrimidine core structure. The structure-activity relationship study indicated that hydrogen, methanesulfonyl, and aminosulfonyl groups substituted at the piperidinylamino functionality provide high inhibitory activity against IKK-2. Also, morpholinosulfonyl and piperazinosulfonyl group substituted at the aromatic ring attached to the aminopyrimidine core significantly increased the inhibitory activity of the resulting derivatives. In particular, compound 17 with the aromatic piperazinosulfonyl substituent showed the most potent (IC50 = 1.30 mu M) and selective (over other kinases such as p38 alpha, p38 beta, JNK1, JNK2, JNK3, and IKK-1) inhibitory activity against IKK-2. (C) 2011 Elsevier Ltd. All rights reserved.
Keywords
NF-KAPPA-B; RHEUMATOID-ARTHRITIS; BETA INHIBITORS; IN-VITRO; IDENTIFICATION; LEFLUNOMIDE; ACTIVATION; DESIGN; CANCER; AP-1; NF-KAPPA-B; RHEUMATOID-ARTHRITIS; BETA INHIBITORS; IN-VITRO; IDENTIFICATION; LEFLUNOMIDE; ACTIVATION; DESIGN; CANCER; AP-1; Rheumatoid arthritis; Inflammation; Aminopyrimidine; IKK-2; Kinase inhibitor
ISSN
0960-894X
URI
https://pubs.kist.re.kr/handle/201004/130353
DOI
10.1016/j.bmcl.2011.03.044
Appears in Collections:
KIST Article > 2011
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