Hoegenauer, Klemens, Soldermann, Nicolas, Hebach, Christina, Hollingworth, Greg, Lewis, Ian, Von Matt, Anette, Smith, Alexander Baxter, Wolf, Romain, Wilcken, Rainer, Haasen, Dorothea, Burkhart, Christoph and Zecri, Frederic (2016) Discovery of novel pyrrolidineoxy-substituted heteroaromatics as potent and selective PI3K delta inhibitors with improved physicochemical properties. Bioorganic and medicinal chemistry letters, 26 (23). pp. 5657-5662. ISSN 0960-894X

Abstract

In the recent years, PI3Kδ has emerged as a promising target for the treatment of B- and T-cell mediated inflammatory diseases. A detailed analysis of our previously reported 4,6-diaryl quinazoline PI3Kδ inhibitor series revealed that the activity in cellular assays was logP dependent, with an optimum logP range between 2-3. We discovered novel analogues in this lipophilicity space that feature a chiral pyrrolidineoxy-group instead of one of the aromatic rings. Compared to 4,6-diaryl quinazolines, these Fsp3 enriched derivatives retain potency and selectivity towards PI3Kδ, yet their permeability profile is improved and molecular weight as well as PSA are reduced. These modifications offer additional possibilities for derivative generation in a good physicochemical property space and thus increase the chances to identify a clinical candidate.

Item Type:	Article
Date Deposited:	22 Nov 2016 00:45
Last Modified:	22 Nov 2016 00:45
URI:	https://oak.novartis.com/id/eprint/31078