Journal of Medicinal Chemistry p. 5245 - 5256 (2018)
Update date:2022-09-26
Topics:
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.
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.
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