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Discovery and Pharmacological Characterization of Novel Quinazoline-based PI3K delta-selective Inhibitors

Hoegenauer, Klemens and Soldermann, Nicolas and Stauffer, Frederic and Furet, Pascal and Graveleau, Nadege and Smith, Alexander Baxter and Hebach, Christina and Hollingworth, Greg and Lewis, Ian and Gutmann, Sascha and Rummel, Gabriele and Knapp, Mark and Wolf, Romain and Blanz, Joachim and Feifel, Roland and Burkhart, Christoph and Zecri, Frederic (2016) Discovery and Pharmacological Characterization of Novel Quinazoline-based PI3K delta-selective Inhibitors. ACS Medicinal Chemistry Letters. ISSN 1948-58751948-5875

Abstract

Inhibition of the lipid kinase PI3K-delta is a promising principle to treat B- and T-cell driven inflammatory diseases. Using a scaffold deconstruction–reconstruction strategy, we identified 4-aryl quinazolines that were optimized into potent and PI3K-delta isoform selective analogues with good pharmacokinetic properties. With compound 11, we illustrate that biochemical PI3K-delta inhibition translates into modulation of isoform dependent immune cell function (human, rat and mouse). After oral administration of compound 11 to rats, proximal PD markers are inhibited, and dose-dependent efficacy in a mechanistic plaque forming cell assay could be demonstrated.

Item Type: Article
Date Deposited: 14 Jun 2016 23:45
Last Modified: 04 Jul 2016 23:45
URI: https://oak.novartis.com/id/eprint/29434

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