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)

Journal of Medicinal Chemistry
Jon ComeAlex M Aronov

Abstract

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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Citations

Mar 1, 2019·Biomolecules·Michelle S MillerSandra B Gabelli
Jan 23, 2021·Journal of Medicinal Chemistry·Zhouling XieChenzhong Liao
Oct 16, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yoshihide UsamiShinya Harusawa
Jun 16, 2021·Nature Reviews. Drug Discovery·Bart VanhaesebroeckKlaus Okkenhaug
Nov 21, 2020·ACS Medicinal Chemistry Letters·Dillon H MilesJenna L Jeffrey
Sep 1, 2020·Journal of Medicinal Chemistry·Samuel L DrewJenna L Jeffrey
Jan 26, 2021·ACS Medicinal Chemistry Letters·Upul K BandarageJinwang Xu
Dec 26, 2018·Journal of Medicinal Chemistry·Aimie E Garces, Michael J Stocks
Dec 26, 2018·Journal of Medicinal Chemistry·Matthew W D PerryAnnika Westin Eriksson

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