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

• Published in: International journal of peptide research and therapeutics Vol. 26; no. 3; pp. 1383 - 1397
• Main Authors: Vorherr, Thomas, Lewis, Ian, Berghausen, Joerg, Huth, Felix, Schaefer, Michael, Wille, Roman, Gao, Jinhai, Wang, Bing
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.09.2020; Springer Nature B.V
• 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; Cyclic peptide; Oral bioavailability; Permeability; Pharmacokinetics; Conformation
• ISSN: 1573-3149; 1573-3904
• DOI: 10.1007/s10989-019-09935-y

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