A cassette-dosing approach for improvement of oral bioavailability of dual TACE/MMP inhibitors.
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.
Janser
Philipp
P
Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. philipp.janser@novartis.com
Neumann
Ulf
U
Miltz
Wolfgang
W
Feifel
Roland
R
Buhl
Thomas
T
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
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