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Bioorg Med Chem Lett. 2006 May 15;16(10):2632-6. Epub 2006 Mar 3.

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

Author information

1
Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. philipp.janser@novartis.com

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.

PMID:
16516469
DOI:
10.1016/j.bmcl.2006.02.042
[Indexed for MEDLINE]

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