Pyridyl-Ala Modified Cyclic Hexapeptides: In-Vitro and In-Vivo Profiling for Oral Bioavailability

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...

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Bibliographic Details
Published in:International journal of peptide research and therapeutics 2020-09, Vol.26 (3), p.1383-1397
Main Authors: Vorherr, Thomas, Lewis, Ian, Berghausen, Joerg, Huth, Felix, Schaefer, Michael, Wille, Roman, Gao, Jinhai, Wang, Bing
Format: Article
Language:English
Subjects:
Amino acids
Animal Anatomy
Bioavailability
Biochemistry
Biomedical and Life Sciences
Histology
Life Sciences
Molecular Medicine
Morphology
NMR
Nuclear magnetic resonance
Permeability
Pharmaceutical Sciences/Technology
Pharmacology/Toxicology
Polymer Sciences
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Summary: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. Graphic Abstract
ISSN:1573-3149
1573-3904
DOI:10.1007/s10989-019-09935-y