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Discovery and Pharmacological Characterization of Novel Quinazoline-Based PI3K Delta-Selective Inhibitors.

ABSTRACT: Inhibition of the lipid kinase PI3K? 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 PI3K? isoform selective analogues with good pharmacokinetic properties. With compound 11, we illustrate that biochemical PI3K? 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.

SUBMITTER: Hoegenauer K

PROVIDER: S-EPMC4983741 | biostudies-other | 2016 Aug

REPOSITORIES: biostudies-other

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Discovery and Pharmacological Characterization of Novel Quinazoline-Based PI3K Delta-Selective Inhibitors.

Hoegenauer Klemens K Soldermann Nicolas N Stauffer Frédéric F Furet Pascal P Graveleau Nadege N Smith Alexander B AB Hebach Christina C Hollingworth Gregory J GJ Lewis Ian I Gutmann Sascha S Rummel Gabriele G Knapp Mark M Wolf Romain M RM Blanz Joachim J Feifel Roland R Burkhart Christoph C Zécri Frédéric F

ACS medicinal chemistry letters 20160602 8

Inhibition of the lipid kinase PI3Kδ 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 PI3Kδ isoform selective analogues with good pharmacokinetic properties. With compound 11, we illustrate that biochemical PI3Kδ inhibition translates into modulation of isoform-dependent immune cell function (human, rat, and mouse). After oral administration of co ...[more]

PMID: 27563400

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