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Pharmacokinetic Studies around the Mono‐ and Difunctionalization of a Bioavailable Cyclic Decapeptide Scaffold
Author(s) -
Fouché Marianne,
Schäfer Michael,
Blatter Markus,
Berghausen Jörg,
Desrayaud Sandrine,
Roth HansJörg
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600083
Subject(s) - bioavailability , scaffold , pharmacokinetics , chemistry , pharmacology , combinatorial chemistry , stereochemistry , medicine , biomedical engineering
We previously reported the design of several cyclic decapeptides based on a generic scaffold that achieved favorable oral bioavailability and exposure. With the goal to further investigate the potential of this approach, we describe herein the effect of mono‐ and difunctionalization of this scaffold. A series of cyclic decapeptides were therefore subjected to a range of in vitro assays and pharmacokinetic (PK) studies to investigate whether the introduction of polar or charged groups could be tolerated by the “engineered” scaffold while maintaining good PK profiles. Whereas the introduction of charged amino acids proved—besides maintaining low clearance—to conceal the inherent PK properties of the scaffold, the introduction of polar amino acids (i.e., threonine and pyridyl alanine) led to several cyclic decapeptides exhibiting excellent PK profiles together with a solubility that was significantly improved relative to that of previously reported cyclic decapeptides.