A cassette-dosing approach for improvement of oral bioavailability of dual TACE/MMP inhibitors

Bioorganic & Medicinal Chemistry Letters
Philipp JanserThomas Buhl

Abstract

The structural features contributing to the different pharmacokinetic properties of the TACE/MMP inhibitors TNF484 and Trocade were analyzed using an in vivo cassette-dosing approach in rats. This enabled us to identify a new lead compound with excellent pharmacokinetic properties, but weaker activity on the biological targets. Directed structural modifications maintained oral bioavailability and restored biological activity, leading to a novel compound almost equipotent to TNF484 in vivo, but with a more than tenfold higher oral bioavailability.

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Citations

Apr 28, 2012·Nature Protocols·Michal SzostakDavid J Procter
Oct 23, 2010·European Journal of Medicinal Chemistry·Emanuele AttolinoCristina Nativi
Mar 10, 2017·Bioorganic & Medicinal Chemistry Letters·Gilles OuvryLaurent F Hennequin
Feb 20, 2007·Molecular Cancer Therapeutics·Nicola F SmithPaul Workman

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