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.
Klemens Hoegenauer  1 ,  Nicolas Soldermann  1 ,  Frédéric Stauffer  1 ,  Pascal Furet  1 ,  Nadege Graveleau  1 ,  Alexander B Smith  1 ,  Christina Hebach  1 ,  Gregory J Hollingworth  1 ,  Ian Lewis  1 ,  Sascha Gutmann  1 ,  Gabriele Rummel  1 ,  Mark Knapp  2 ,  Romain M Wolf  1 ,  Joachim Blanz  1 ,  Roland Feifel  1 ,  Christoph Burkhart  1 ,  Frédéric Zécri  1
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.
PMID: 27563400 DOI: 10.1021/acsmedchemlett.6b00119
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.
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