title: Discovery and Pharmacological Characterization of Novel Quinazoline-Based PI3K Delta-Selective Inhibitors.
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.
authors: 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.
authors: Klemens
authors: K
authors: Hoegenauer
authors: 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.
authors: Nicolas
authors: N
authors: Soldermann
authors: 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.
authors: Frédéric
authors: F
authors: Stauffer
authors: 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.
authors: Pascal
authors: P
authors: Furet
authors: 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.
authors: Nadege
authors: N
authors: Graveleau
authors: 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.
authors: Alexander B
authors: AB
authors: Smith
authors: 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.
authors: Christina
authors: C
authors: Hebach
authors: 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.
authors: Gregory J
authors: GJ
authors: Hollingworth
authors: 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.
authors: Ian
authors: I
authors: Lewis
authors: 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.
authors: Sascha
authors: S
authors: Gutmann
authors: 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.
authors: Gabriele
authors: G
authors: Rummel
authors: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors: Mark
authors: M
authors: Knapp
authors: 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.
authors: Romain M
authors: RM
authors: Wolf
authors: 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.
authors: Joachim
authors: J
authors: Blanz
authors: 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.
authors: Roland
authors: R
authors: Feifel
authors: 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.
authors: Christoph
authors: C
authors: Burkhart
authors: 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.
authors: Frédéric
authors: F
authors: Zécri
keywords: B cell inhibition; PI3Kδ inhibitor; PK/PD studies; Phosphoinositide-3-kinase delta inhibitor; lead optimization; structure−activity relationship