title: Discovery of piperidinyl aminopyrimidine derivatives as IKK-2 inhibitors.
abstract: A serine-threonine kinase IKK-2 plays an important role in activation of NF-κB through phosphorylation of the inhibitor of NF-κB (IκB). As NF-κB 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 μM) and selective (over other kinases such as p38α, p38β, JNK1, JNK2, JNK3, and IKK-1) inhibitory activity against IKK-2.
authors.affiliation: Life/Health Division, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: Sora
authors.initials: S
authors.lastname: Kim
authors.forename: Jin Kyo
authors.initials: JK
authors.lastname: Jung
authors.forename: Hyo Seon
authors.initials: HS
authors.lastname: Lee
authors.forename: Youngjae
authors.initials: Y
authors.lastname: Kim
authors.forename: Jiyoon
authors.initials: J
authors.lastname: Kim
authors.forename: Kihang
authors.initials: K
authors.lastname: Choi
authors.forename: Du-Jong
authors.initials: DJ
authors.lastname: Baek
authors.forename: Bongjin
authors.initials: B
authors.lastname: Moon
authors.forename: Kwang-Seok
authors.initials: KS
authors.lastname: Oh
authors.forename: Byung Ho
authors.initials: BH
authors.lastname: Lee
authors.forename: Kye Jung
authors.initials: KJ
authors.lastname: Shin
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
authors.forename: Ghilsoo
authors.initials: G
authors.lastname: Nam
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Roh
authors.forename: Yong Seo
authors.initials: YS
authors.lastname: Cho
authors.forename: Hyunah
authors.initials: H
authors.lastname: Choo
mesh_terms: D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D010880:Piperidines; D011743:Pyrimidines; C034821:4-aminopyrimidine; D051550:I-kappa B Kinase