Discovery of novel pyrrolidineoxy-substituted heteroaromatics as potent and selective PI3K delta inhibitors with improved physicochemical properties.
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 Fsp3enriched 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.
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland. Electronic address: klemens.hoegenauer@novartis.com.
Klemens
K
Hoegenauer
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Nicolas
N
Soldermann
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Christina
C
Hebach
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Gregory J
GJ
Hollingworth
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Ian
I
Lewis
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Anette
A
von Matt
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Alexander B
AB
Smith
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Romain M
RM
Wolf
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Rainer
R
Wilcken
Center for Proteomic Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Dorothea
D
Haasen
Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Christoph
C
Burkhart
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Frédéric
F
Zécri
D000818:Animals; D058534:Class I Phosphatidylinositol 3-Kinases; D055808:Drug Discovery / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D057075:Enzyme Assays / Q000379:methods; D006801:Humans; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats
D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011759:Pyrrolidines; D011799:Quinazolines; C421683:Pik3cd protein, mouse; C032519:pyrrolidine
Lipophilicity; PI3Kδ inhibitor; Phosphoinositide-3-kinase delta inhibitor; Physicochemical properties; Structure-activity relationship