MEDI 466 |
| PI3Kgamma is a key enzyme in leukocyte signalling, essentially responsible for mediating chemotaxis of leukocytes as well as degranulation of mast cells. PI3Kgamma functions mainly in response to G-protein coupled receptor activation and hence represents a high value target for autoimmunity and inflammation. There is an underlying body of evidence that inhibition of PI3Kgamma could be beneficial for the treatment of Rheumatoid Arthritis (RA). We have previously published potent, selective PI3Kgamma inhibitors orally active in murine models of RA (e.g. collagen induced arthritis, CIA). Our PI3Kgamma inhibitors suppress the progression of joint inflammation and cartilage damage. Here, we present a second generation of azolidinone vinyl-fused heteroaromatic derivatives as potent PI3Kgamma inhibitors with an improved pharmacokinetic and pharmacodynamic profile. Our Medicinal Chemistry efforts have led to the identification of a development candidate cpd 23, a potent PI3Kgamma inhibitor, which is fully orally available and shows efficacy in a mouse CIA model at 1mg/kg upon oral treatment. |
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General Oral Session
1:30 PM-4:50 PM, Thursday, August 23, 2007 BCEC -- 210A, Oral
Division of Medicinal Chemistry |