Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3-Kinase (PI3K)-γ Inhibitors

Journal of Medicinal Chemistry
Nils PembertonLinda Öster

Abstract

In this paper, we describe the discovery and optimization of a new chemotype of isoform selective PI3Kγ inhibitors. Starting from an HTS hit, potency and physicochemical properties could be improved to give compounds such as 15, which is a potent and remarkably selective PI3Kγ inhibitor with ADME properties suitable for oral administration. Compound 15 was advanced into in vivo studies showing dose-dependent inhibition of LPS-induced airway neutrophilia in rats when administered orally.

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Citations

Mar 1, 2019·Biomolecules·Michelle S MillerSandra B Gabelli
Jul 30, 2019·Frontiers in Immunology·Nadège BercoviciEmmanuel Donnadieu
Feb 6, 2019·Nature Chemical Biology·Gangadhara GangadharaJens Petersen
Oct 4, 2019·European Journal of Medicinal Chemistry·Fatma M ElmenierKhaled A M Abouzid
Jun 4, 2021·Journal of Medicinal Chemistry·Matthew W D PerryLinda Öster
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
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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