Discovery of novel pyrrolidineoxy-substituted heteroaromatics as potent and selective PI3K delta inhibitors with improved physicochemical properties
| Autor: | Nicolas Soldermann, Ian Lewis, Alexander Baxter Smith, Klemens Hoegenauer, Frédéric Zecri, Dorothea Haasen, Anette Von Matt, Gregory Hollingworth, Christoph Burkhart, Christina Hebach, Rainer Wilcken, Romain M. Wolf |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pyrrolidines Class I Phosphatidylinositol 3-Kinases Stereochemistry Clinical Biochemistry Drug Evaluation Preclinical Pharmaceutical Science 01 natural sciences Biochemistry Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences chemistry.chemical_compound Drug Discovery Quinazoline Animals Humans Structure–activity relationship Protein Kinase Inhibitors Molecular Biology PI3K/AKT/mTOR pathway Enzyme Assays Phosphoinositide-3 Kinase Inhibitors Organic Chemistry Combinatorial chemistry Rats 0104 chemical sciences 010404 medicinal & biomolecular chemistry 030104 developmental biology chemistry Lipophilicity Quinazolines Molecular Medicine Selectivity |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 26:5657-5662 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2016.10.069 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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