Author/Authors :
Matthew J. Laufersweiler، نويسنده , , Todd A Brugel، نويسنده , , Michael P Clark، نويسنده , , Adam Golebiowski، نويسنده , , Roger G. Bookland، نويسنده , , Steven K Laughlin، نويسنده , , Mark P Sabat، نويسنده , , Jennifer A Townes، نويسنده , , John C. VanRens، نويسنده , , Biswanath De، نويسنده , , Lily C. Hsieh، نويسنده , , Sandra A Heitmeyer، نويسنده , , Karen Juergens، نويسنده , , Kimberly K Brown، نويسنده , , Marlene J Mekel، نويسنده , , Richard L. Walter and Alan M. Friedman، نويسنده , , Michael J Janusz، نويسنده ,
Abstract :
Novel substituted [5,5]-bicyclic pyrzazolones are presented as inhibitors of tumor necrosis factor-α (TNF-α) production. Many of these compounds show low nanomolar activity against lipopolysaccaride (LPS)-induced TNF-α production in THP-1 cells. This class of molecules was co-crystallized with mutated p38, and several analogs showed good oral bioavailability in the rat. Oral activity of these compounds in the rat iodoacetate model for osteoarthritis is discussed.
Keywords :
TNF-A , p38 , Cytokine synthesis inhibition , Pyrazolones , Kinases.
