Quinoline Biochemistry 2016

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∥, and Frédéric Zécri†

^†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

^⊥ Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, California 94608, United States

ACS Med. Chem. Lett., 2016, 7 (8), pp 762–767

DOI: 10.1021/acsmedchemlett.6b00119

Publication Date (Web): June 2, 2016

Copyright © 2016 American Chemical Society

*(K.H.) Tel: +41 79 6181814. E-mail: klemens.hoegenauer@novartis.com., *(N.S.) Tel: +41 79 8451506. E-mail: nicolas.soldermann@novartis.com.

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; lead optimization; Phosphoinositide-3-kinase delta inhibitor; PI3Kδ inhibitor; PK/PD studies; structure−activity relationship

Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.6b00119.

• Full descriptions of all biological assays and in vivo studies. Characterization of all compounds. Full experimental procedures for the sequence leading to compound 11. Crystallographic data collection and refinement statistics for crystal structures (PDF)

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