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Pyridyl-Ala modified cyclic hexapeptides: in-vitro and in-vivo profiling for oral bioavailability

Vorherr, Thomas and Lewis, Ian and Berghausen, Joerg and Huth, Felix and Schaefer, Michael and Wille, Roman Mariano and Gao, Jinhai and Wang, Bing (2019) Pyridyl-Ala modified cyclic hexapeptides: in-vitro and in-vivo profiling for oral bioavailability. International journal of peptide research and therapeutics., 19 (4). pp. 275-380. ISSN 1573-3149

Abstract

We and others have been aiming at modifications to maintain or to enhance solubility while enabling permeability for cyclic hexapeptides. Especially, the 2-pyridyl-Ala modification was investigated, since in this case, the pyridyl-nitrogen is able to form an H-bond to the NH of the same residue. The hypothesis of a backbone side-chain interaction was demonstrated by NMR experiments, and further results obtained on a variety of pyridyl-Ala derivatives, studied systematically in the context of permeability, are presented in this contribution. Thus, this study sheds some more light on the pyridyl-Ala modification, which had been reported earlier. In addition to the in-vitro profiling, the extent of oral bioavailability was assessed in rats. In principle, the pyridyl-Ala residue can be considered as an amino acid supporting oral uptake.

Item Type: Article
Keywords: Conformation, cyclic peptide, oral bioavailability, permeability, pharmacokinetics
Date Deposited: 09 Nov 2019 00:45
Last Modified: 09 Nov 2019 00:45
URI: https://oak.novartis.com/id/eprint/39684

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