Increasing metabolic stability via the deuterium kinetic isotope effect: An example from a proline-amide-urea aminothiazole series of phosphatidylinositol-3 kinase alpha inhibitors
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- 作者：Robin A. Fairhurst ; robin.fairhurst@novartis.com" class="auth_mail" title="E-mail the corresponding author ; Giorgio Caravatti ; Vito Guagnano ; Reiner Aichholz ; Joachim Blanz ; Francesca Blasco ; Peter Wipfli ; Christine Fritsch ; Sauveur-Michel Maira ; Christian Schnell ; Frank H. Seiler
- 关键词：Phosphatidylinositol-3 kinase alpha inhibitor ; Deuterium kinetic isotope effect ; Metabolism ; Pharmacokinetics
- 刊名：Bioorganic & Medicinal Chemistry Letters
- 出版年：2016
- 出版时间：1 October 2016
- 年：2016
- 卷：26
- 期：19
- 页码：4729-4734
- 全文大小：1135 K
文摘
In vitro metabolic identification studies with a PI3K-α inhibitor lead molecule 1 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 molecule 1, to the corresponding 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.