- Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3-Kinase γ (PI3Kγ) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS)
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The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.
- Come, Jon H.,Collier, Philip N.,Henderson, James A.,Pierce, Albert C.,Davies, Robert J.,Le Tiran, Arnaud,O'Dowd, Hardwin,Bandarage, Upul K.,Cao, Jingrong,Deininger, David,Grey, Ron,Krueger, Elaine B.,Lowe, Derek B.,Liang, Jianglin,Liao, Yusheng,Messersmith, David,Nanthakumar, Suganthi,Sizensky, Emmanuelle,Wang, Jian,Xu, Jinwang,Chin, Elaine Y.,Damagnez, Veronique,Doran, John D.,Dworakowski, Wojciech,Griffith, James P.,Jacobs, Marc D.,Khare-Pandit, Suvarna,Mahajan, Sudipta,Moody, Cameron S.,Aronov, Alex M.
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- ISOINDOLINONE INHIBITORS OF PHOSPHATIDYLINOSITOL 3-KINASE
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The present invention relates to compounds useful as inhibitors of PI3K, particularly of PI3Kγ. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.
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(2011/08/04)
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