Discovery of piperidinyl aminopyrimidine derivatives as IKK-2 inhibitors

作者：Kim Sora; Jung Jin Kyo; Lee Hyo Seon; Kim Youngjae; Kim Jiyoon; Choi Kihang; Baek Du Jong; Moon Bongjin; Oh Kwang Seok; Lee Byung Ho; Shin Kye Jung; Pae Ae Nim; Nam Ghilsoo; Roh Eun Joo; Cho Yong Seo; Choo Hyunah^*

来源：Bioorganic & Medicinal Chemistry Letters, 2011, 21(10): 3002-3006.

DOI：10.1016/j.bmcl.2011.03.044

• Rheumatoid arthritis
• Inflammation
• Aminopyrimidine
• IKK-2
• Kinase inhibitor

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 (IC(50) = 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.

• 出版日期2011-5-15