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.

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