2. Academic Validation
  3. Discovery and Pharmacological Characterization of Novel Quinazoline-Based PI3K Delta-Selective Inhibitors

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-125376
    PI3Kδ抑制剂
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