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

Pemberton, N and Mogemark, M and Arlbrandt, S and Bold, P and Cox, RJ and Gardelli, C and Holden, Neil and Karabelas, K and Karlsson, J and Lever, J and Li, X and Lindmark, H and Norberg, M and Perry, MWD and Petersen, J and Rodrigo Blomqvist, S and Thomas, M and Tyrchan, C and Westin Eriksson, A and 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: https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b00...

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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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