Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 22, Issue 17, Pages 5668-5674Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2012.06.088
Keywords
IKK beta inhibitor; NF-kappa B; TNF alpha; Reumatoid athritis; Hit-to-lead
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Funding
- Catholic University of Korea
- National Research Foundation of Korea (NRF)
- Ministry of Education, Science and Technology
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Regulation of NF-kappa B activation through the inhibition of IKK beta has been identified as a promising target for the treatment of inflammatory and autoimmune disease such as rheumatoid arthritis. In order to develop novel IKK beta inhibitors, we performed high throughput screening toward around 8000 library compounds, and identified a hit compound containing rhodanine moiety. We modified the structure of hit compound to obtain potent and selective IKK beta inhibitors. Throughout hit-to-lead studies, we have discovered optimized compounds which possess blocking effect toward NF-kappa B activation and TNF alpha production in cell as well as inhibition activity against IKK beta. Among them, compound 3q showed the potent inhibitory activity against IKK beta, and excellent selectivity over other kinases such as p38 alpha, p38 beta, JNK1, JNK2, and JNK3 as well as IKK alpha. (C) 2012 Elsevier Ltd. All rights reserved.
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