Synthesis and structure–activity relationships of novel IKK-β inhibitors. Part 2: Improvement of in vitro activity

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 15; pp. 4013 - 4017
• Main Authors: Murata, Toshiki, Shimada, Mitsuyuki, Kadono, Hiroshi, Sakakibara, Sachiko, Yoshino, Takashi, Masuda, Tsutomu, Shimazaki, Makoto, Shintani, Takuya, Fuchikami, Kinji, Bacon, Kevin B, Ziegelbauer, Karl B, Lowinger, Timothy B
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 02.08.2004; Elsevier
• Subjects: Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; I-kappa B Kinase; IKK-β; Kinase inhibitor; Kinetics; Medical sciences; Models, Molecular; Molecular Conformation; NF-κB; Pharmacology. Drug treatments; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Recombinant Proteins - antagonists & inhibitors; Structure-Activity Relationship; NF-κB; IKK-β; Kinase inhibitor; Nitrile; Enzyme; Transferases; Enzyme inhibitor; In vitro; Pyridine derivatives; Signal transduction; Structure activity relation; Kinase; Protein kinase; Aromatic compound; Transcription factor NFκB; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.05.040

Graphic A series of 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl)pyridine derivatives was synthesized and evaluated as IκB kinase β (IKK-β) inhibitors. Substitution of an aminoalkyl group for the aromatic group at the 4-position on the core pyridine ring resulted in a marked increase in both kinase enzyme and cellular potencies, and provided potent IKK-β inhibitors with IC 50 values of below 100 nM.