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Increasing metabolic stability via the deuterium kinetic isotope effect: an example from a proline-amide-urea aminothiazole series of phosphatidylinositol-3 kinase alpha inhibitors

Caravatti, Giorgio and Guagnano, Vito and Aichholz, Reiner and Blanz, Joachim and Blasco, Francesca and Wipfli, Peter and Fritsch, Christine and Maira, Sauveur-Michel and Schnell, Christian and Seiler, Frank Hans (2016) Increasing metabolic stability via the deuterium kinetic isotope effect: an example from a proline-amide-urea aminothiazole series of phosphatidylinositol-3 kinase alpha inhibitors. Bioorganic and Medicinal Chemistry Letters, 26 (19). pp. 4729-4734. ISSN 0960-894X

Abstract

In vitro metabolic identification studies with a PI3K-α inhbitor lead molecule 1 identified a single predominant site of oxidative metabolism to be occuring within a tert.butyl moiety. Modification of the tert.butyl group within the lead molecule 1, to the corresponing d9-tert.butyl analogue 2, 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, for 2 when compared to 1.

Item Type: Article
Keywords: Phosphatidylinositol-3 kinase alpha inhibitor, deuterium kinetic isotope effect, metabolism, pharmacokinetics
Date Deposited: 04 Oct 2016 00:45
Last Modified: 04 Oct 2016 00:45
URI: https://oak.novartis.com/id/eprint/29711

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