title: Increasing metabolic stability via the deuterium kinetic isotope effect: An example from a proline-amide-urea aminothiazole series of phosphatidylinositol-3 kinase alpha inhibitors.
abstract: 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.
authors: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. Electronic address: robin.fairhurst@novartis.com.
authors: Robin A
authors: RA
authors: Fairhurst
authors: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors: Giorgio
authors: G
authors: Caravatti
authors: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors: Vito
authors: V
authors: Guagnano
authors: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors: Reiner
authors: R
authors: Aichholz
authors: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors: Joachim
authors: J
authors: Blanz
authors: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors: Francesca
authors: F
authors: Blasco
authors: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors: Peter
authors: P
authors: Wipfli
authors: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors: Christine
authors: C
authors: Fritsch
authors: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors: Sauveur-Michel
authors: SM
authors: Maira
authors: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors: Christian
authors: C
authors: Schnell
authors: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors: Frank H
authors: FH
authors: Seiler
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D001682:Biological Availability; D058534:Class I Phosphatidylinositol 3-Kinases; D003903:Deuterium / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D007700:Kinetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011392:Proline / Q000737:chemistry; D051381:Rats; D013844:Thiazoles / Q000737:chemistry; D014508:Urea / Q000737:chemistry
chemical_list: D000577:Amides; D058534:Class I Phosphatidylinositol 3-Kinases; D003903:Deuterium; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011392:Proline; D013844:Thiazoles; D014508:Urea; C484760:PIK3CA protein, human
keywords: Deuterium kinetic isotope effect; Metabolism; Pharmacokinetics; Phosphatidylinositol-3 kinase alpha inhibitor