The phosphoinositide 3-kinases (PI3Ks) catalyze the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) as part of the canonical PI3K/AKT/mTOR pathway. Recently, the class I isoform PI3Kγ has been identified as an immuno-oncology target because it has been shown to exert control on the tumor microenvironment primarily through effects in macrophages. Herein, we report the discovery of a series of aryl sulfonamides as potent and selective PI3Kγ inhibitors. The campaign initiated with the evaluation of more than 50 fragments. In an effort to reduce aromatic character, an initial lead was cyclized and reduced resulting in a newly designed fragment, which was a small, ligand-efficient inhibitor. Subsequent structure-based design guided installation of the sulfonamide, which improved potency by greater than 50-fold, while further SAR efforts drove the potency to acceptable levels. Profiling of these early compounds identified two significant metabolic hotspots on the sulfonamide substituent. Gratifyingly, the incorporation of a bridged bicyclic substituent reduced <i>in vivo</i> metabolism and in some cases also improved potency. Finally, isolation and NMR characterization of a major metabolite from this bicyclic series confirmed that the tolyl methyl group was now the primary site of oxidative metabolism. Harnessing the kinetic isotope effect, deuteration of the methyl group further reduced the intrinsic clearance and improved the pharmacokinetic properties, which resulted in the identification of a key compound that was advanced into further studies.

Discovery of potent and selective PI3Kγ inhibitors via elaboration of a designed fragment and identification of key metabolites

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.