title: Optimization and biological evaluation of aminopyrimidine-based IκB kinase β inhibitors with potent anti-inflammatory effects.
abstract: Targeting IκB kinase β (IKKβ) can be a promising strategy in the development of a therapeutic treatment of inflammatory diseases because IKKβ is well-recognized as a key mediator of the NF-κB signaling pathway. In this study, we have successfully developed a structure-activity relationship (SAR) profile of the aminopyrimidine-based IKKβ inhibitors through the structure-based design strategy to improve the physicochemical properties and cellular activity in terms of the anti-inflammatory effects. Representative compounds exhibited desirable activity in nitric oxide (NO) reduction by inhibiting the synthesis of inducible nitric oxide synthase (iNOS), and strongly inhibited the expression of pro-inflammatory cytokines (IL-1α, IL-6, and TNF-α). The inhibitory effects of 8e on the phosphorylation in the NF-κB pathway further supported that the suppression of the NF-κB signaling pathway induced the anti-inflammatory effect in LPS-stimulated Raw 264.7 cells.
authors: Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea; Center for Catalytic Hydrocarbon Functionalizations, Institute of Basic Science (IBS), Daejeon 34141, South Korea.
authors: Yongje
authors: Y
authors: Shin
authors: Center for Catalytic Hydrocarbon Functionalizations, Institute of Basic Science (IBS), Daejeon 34141, South Korea; Korea Institute of Science and Technology (KIST), Seoul 02792, South Korea.
authors: Sang Min
authors: SM
authors: Lim
authors: Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 400-712, South Korea.
authors: Hong Hua
authors: HH
authors: Yan
authors: Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea; Center for Catalytic Hydrocarbon Functionalizations, Institute of Basic Science (IBS), Daejeon 34141, South Korea.
authors: Sungwoo
authors: S
authors: Jung
authors: Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 400-712, South Korea.
authors: Zhenghuan
authors: Z
authors: Fang
authors: Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 400-712, South Korea.
authors: Kyung Hee
authors: KH
authors: Jung
authors: Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 400-712, South Korea. Electronic address: hongs@inha.ac.kr.
authors: Soon-Sun
authors: SS
authors: Hong
authors: Center for Catalytic Hydrocarbon Functionalizations, Institute of Basic Science (IBS), Daejeon 34141, South Korea; Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea. Electronic address: hongorg@kaist.ac.kr.
authors: Sungwoo
authors: S
authors: Hong
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D015195:Drug Design; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D051379:Mice; D008958:Models, Molecular; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D000067996:RAW 264.7 Cells; D015398:Signal Transduction / Q000187:drug effects; D012997:Solvents / Q000737:chemistry
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012997:Solvents; C012180:2-aminopyrimidine; D009569:Nitric Oxide; D051550:I-kappa B Kinase
keywords: Anti-inflammatory effect; IKKβ; Inhibitor; NO reduction; Structure-activity relationship