Janser, Philipp, Neumann, Ulf, Miltz, Wolfgang, 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
Related URLs:	http://www.ncbi.nlm.nih.gov/sites/entrez... doi:10.1016/j.bmcl.2006.02.042
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
Related URLs:	http://www.ncbi.nlm.nih.gov/sites/entrez... doi:10.1016/j.bmcl.2006.02.042
Date Deposited:	14 Dec 2009 14:00
Last Modified:	31 Jan 2013 01:17
URI:	https://oak.novartis.com/id/eprint/427