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

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).