2. Academic Validation
  3. Discovery of novel pyrrolidineoxy-substituted heteroaromatics as potent and selective PI3K delta inhibitors with improved physicochemical properties

Discovery of novel pyrrolidineoxy-substituted heteroaromatics as potent and selective PI3K delta inhibitors with improved physicochemical properties

  • Bioorg Med Chem Lett. 2016 Dec 1;26(23):5657-5662. doi: 10.1016/j.bmcl.2016.10.069.
Klemens Hoegenauer 1,  Nicolas Soldermann 2,  Christina Hebach 2,  Gregory J Hollingworth 2,  Ian Lewis 2,  Anette von Matt 2,  Alexander B Smith 2,  Romain M Wolf 2,  Rainer Wilcken 2,  Dorothea Haasen 3,  Christoph Burkhart 4,  Frédéric Zécri 2
Affiliations

Affiliations

  • 1 Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland. Electronic address: [email protected].
  • 2 Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
  • 3 Center for Proteomic Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
  • 4 Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
PMID: 27816514 DOI: 10.1016/j.bmcl.2016.10.069
Abstract

In the recent years, PI3Kδ has emerged as a promising target for the treatment of B- and T-cell mediated inflammatory diseases. We present a cellular assay activity analysis for our previously reported 4,6-diaryl quinazoline PI3Kδ Inhibitor series that suggests an optimal logP range between 2 and 3. We discovered novel analogues in this lipophilicity space that feature a chiral pyrrolidineoxy-group as a replacement for the position-4 aromatic ring of 4,6-diaryl quinazolines. These Fsp3 enriched derivatives retain potency and selectivity towards PI3Kδ. Compared to 4,6-diaryl quinazolines, their permeability profile is improved and molecular weight as well as PSA are reduced. These modifications offer additional possibilities for derivative generation in a favorable physicochemical property space and thus increase the chances to identify a clinical candidate.

Keywords

Lipophilicity; PI3Kδ inhibitor; Phosphoinositide-3-kinase delta inhibitor; Physicochemical properties; Structure-activity relationship.

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