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Bioorg Med Chem Lett. 2016 Dec 1;26(23):5657-5662. doi: 10.1016/j.bmcl.2016.10.069. Epub 2016 Oct 27.

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

Author information

1
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland. Electronic address: klemens.hoegenauer@novartis.com.
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.

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

PMID:
27816514
DOI:
10.1016/j.bmcl.2016.10.069
[Indexed for MEDLINE]

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