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

Philipp Janser; Ulf Neumann; Wolfgang Miltz; Roland Feifel; Thomas Buhl

doi:10.1016/j.bmcl.2006.02.042

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

Bioorg Med Chem Lett. 2006 May 15;16(10):2632-6. doi: 10.1016/j.bmcl.2006.02.042. Epub 2006 Mar 3.

Authors

Philipp Janser¹, Ulf Neumann, Wolfgang Miltz, Roland Feifel, Thomas Buhl

Affiliation

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

PMID: 16516469
DOI: 10.1016/j.bmcl.2006.02.042

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.

MeSH terms

ADAM Proteins / antagonists & inhibitors*
ADAM17 Protein
Administration, Oral
Animals
Biological Availability
Dose-Response Relationship, Drug
Hydroxamic Acids / administration & dosage
Hydroxamic Acids / pharmacokinetics
Hydroxamic Acids / pharmacology*
Matrix Metalloproteinase Inhibitors*
Protease Inhibitors / administration & dosage
Protease Inhibitors / pharmacokinetics
Protease Inhibitors / pharmacology*
Rats

Substances

Hydroxamic Acids
Matrix Metalloproteinase Inhibitors
N(4)-(2,2-dimethyl-1-methylcarbamoylpropyl)-N(1)-hydroxy-2-hydroxymethyl-3-(4-methoxyphenyl)succinamide
Protease Inhibitors
ADAM Proteins
ADAM17 Protein
Adam17 protein, rat