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

Janser, Philipp and Neumann, Ulf and Miltz, Wolfgang and Feifel, Roland and Buhl, Thomas (2006) A cassette-dosing approach for improvement of oral bioavailability of dual TACE/MMP inhibitors. Bioorganic & Medicinal Chemistry Letters, 16 (10). pp. 2632-2636. ISSN 0960-894X

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.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: TNFα; TACE; MMP; Metalloproteinase; Dual; Inhibitor; Pharmacokinetics; Cassette-dosing; Bioavailability; Oral; Clearance; Absorption; Rheumatoid arthritis; Trocade; TNF484; Claisen–Ireland rearrangement
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Date Deposited: 14 Dec 2009 14:00
Last Modified: 31 Jan 2013 01:17
URI: https://oak.novartis.com/id/eprint/427

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