A cassette-dosing approach for improvement of oral bioavailability of dual TACE/MMP inhibitors.
2006
Abstract The structural features contributing to the different pharmacokinetic properties of the TACE/MMP inhibitors TNF484 and Trocade TM 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.
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