Increasing metabolic stability via the deuterium kinetic isotope effect: An example from a proline-amide-urea aminothiazole series of phosphatidylinositol-3 kinase alpha inhibitors. Issue 19 (1st October 2016)

• Record Type: Journal Article
• Authors: Fairhurst, Robin A.; Caravatti, Giorgio; Guagnano, Vito; Aichholz, Reiner; Blanz, Joachim; Blasco, Francesca; Wipfli, Peter; Fritsch, Christine; Maira, Sauveur-Michel; Schnell, Christian; Seiler, Frank H.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 19(2016)
• Page Start: 4729
• Page End: 4734
• Publication Date: 2016-10-01
• Subjects: Phosphatidylinositol-3 kinase alpha inhibitor -- Deuterium kinetic isotope effect -- Metabolism -- Pharmacokinetics; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.08.041
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: In vitro metabolic identification studies with a PI3K-α inhibitor lead molecule1 identified a single predominant site of oxidative metabolism to be occurring within a tert .butyl moiety. Modification of the tert .butyl group within the lead molecule1, to the corresponding d 9 - tert .butyl analogue2, led to an increase in both the in vitro and in vivo metabolic stability. This increase in metabolic stability resulted in a 2-fold increase in the oral bioavailability measured in the rat, and a 3-fold increase in potency in a chronic in vivo study in the mouse, for2 when compared to1 .