| Literature DB >> 27563400 |
Klemens Hoegenauer1, Nicolas Soldermann1, Frédéric Stauffer1, Pascal Furet1, Nadege Graveleau1, Alexander B Smith1, Christina Hebach1, Gregory J Hollingworth1, Ian Lewis1, Sascha Gutmann1, Gabriele Rummel1, Mark Knapp2, Romain M Wolf1, Joachim Blanz1, Roland Feifel1, Christoph Burkhart1, Frédéric Zécri1.
Abstract
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 compound 11 to rats, proximal PD markers are inhibited, and dose-dependent efficacy in a mechanistic plaque forming cell assay could be demonstrated.Entities:
Keywords: B cell inhibition; PI3Kδ inhibitor; PK/PD studies; Phosphoinositide-3-kinase delta inhibitor; lead optimization; structure−activity relationship
Year: 2016 PMID： 27563400 PMCID： PMC4983741 DOI： 10.1021/acsmedchemlett.6b00119
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345