title: A cassette-dosing approach for improvement of oral bioavailability of dual TACE/MMP inhibitors.
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.
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. philipp.janser@novartis.com
authors.forename: Philipp
authors.initials: P
authors.lastname: Janser
authors.forename: Ulf
authors.initials: U
authors.lastname: Neumann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Miltz
authors.forename: Roland
authors.initials: R
authors.lastname: Feifel
authors.forename: Thomas
authors.initials: T
authors.lastname: Buhl
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats
chemical_list: D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; C455823:N(4)-(2,2-dimethyl-1-methylcarbamoylpropyl)-N(1)-hydroxy-2-hydroxymethyl-3-(4-methoxyphenyl)succinamide; D011480:Protease Inhibitors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat