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

Klemens Hoegenauer; Nicolas Soldermann; Frédéric Stauffer; Pascal Furet; Nadege Graveleau; Alexander B Smith; Christina Hebach; Gregory J Hollingworth; Ian Lewis; Sascha Gutmann; Gabriele Rummel; Mark Knapp; Romain M Wolf; Joachim Blanz; Roland Feifel; Christoph Burkhart; Frédéric Zécri

doi:10.1021/acsmedchemlett.6b00119

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

ACS Med Chem Lett. 2016 Jun 2;7(8):762-7. doi: 10.1021/acsmedchemlett.6b00119. eCollection 2016 Aug 11.

Authors

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

Affiliations

¹ Global Discovery Chemistry, Center for Proteomic Chemistry, Metabolism and Pharmacokinetics, Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research , Novartis Campus, CH-4002 Basel, Switzerland.
² Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.

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.

Keywords: B cell inhibition; PI3Kδ inhibitor; PK/PD studies; Phosphoinositide-3-kinase delta inhibitor; lead optimization; structure−activity relationship.