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

Pemberton, N, Mogemark, M, Arlbrandt, S, Bold, P, Cox, RJ, Gardelli, C, Holden, Neil, Karabelas, K, Karlsson, J, Lever, J, Li, X, Lindmark, H, Norberg, M, Perry, MWD, Petersen, J, Rodrigo Blomqvist, S, Thomas, M, Tyrchan, C, Westin Eriksson, A, Zlatoidsky, P and Öster, L (2018) Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3-Kinase (PI3K)-γ Inhibitors. Journal of Medical Chemistry, 61 (12). pp. 5435-5441. ISSN 0022-2623

Full content URL: http://doi.org/10.1021/acs.jmedchem.8b00447

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

Keywords:PI3K
Subjects:C Biological Sciences > C790 Molecular Biology, Biophysics and Biochemistry not elsewhere classified
Divisions:College of Science > School of Life Sciences
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ID Code:33955
Deposited On:13 Nov 2018 15:20

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