Synthesis and structure–activity relationships of novel IKK-β inhibitors. Part 3: Orally active anti-inflammatory agents

• Published in: Bioorganic & medicinal chemistry letters 2004-08, Vol.14 (15), p.4019-4022
• Main Authors: Murata, Toshiki, Shimada, Mitsuyuki, Sakakibara, Sachiko, Yoshino, Takashi, Masuda, Tsutomu, Shintani, Takuya, Sato, Hiroki, Koriyama, Yuji, Fukushima, Keiko, Nunami, Noriko, Yamauchi, Megumi, Fuchikami, Kinji, Komura, Hiroshi, Watanabe, Akihiko, Ziegelbauer, Karl B, Bacon, Kevin B, Lowinger, Timothy B
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Disease Models, Animal; Edema - prevention & control; Humans; I-kappa B Kinase; IKK-β; Kinase inhibitor; Kinetics; Medical sciences; Mice; Miscellaneous; Models, Molecular; Molecular Structure; NF- κB; Pharmacology. Drug treatments; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Pyridines - chemical synthesis; Pyridines - pharmacology; Recombinant Proteins - antagonists & inhibitors; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.05.041

Graphic A series of 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl)pyridine derivatives was synthesized and evaluated as I κB kinase β (IKK-β) inhibitors. Modification of a novel IKK-β inhibitor 1 (IKK-β IC 50 = 1500 nM, Cell IC 50 = 8000 nM) at the 4-phenyl ring and 6-phenol group on the pyridine core ring resulted in a marked increased in biological activities. An optimized compound, 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile, exhibited excellent in vitro profiles (IKK-β IC 50 = 8.5 nM, Cell IC 50 = 60 nM) and a strong oral efficacy in in vivo anti-inflammatory assays (significant effects at 1 mg/kg, po in arachidonic acid-induced ear edema model in mice).