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
  • 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.