Pharmacokinetic Studies around the Mono- and Difunctionalization of a Bioavailable Cyclic Decapeptide Scaffold

• Published in: ChemMedChem Vol. 11; no. 10; pp. 1060 - 1068
• Main Authors: Fouché, Marianne, Schäfer, Michael, Blatter, Markus, Berghausen, Jörg, Desrayaud, Sandrine, Roth, Hans-Jörg
• Format: Journal Article
• Language: English
• Published: WEINHEIM Blackwell Publishing Ltd 19.05.2016; Wiley; Wiley Subscription Services, Inc
• Subjects: Administration, Oral; Amino acids; Amino Acids - chemistry; Amino Acids - metabolism; Animals; biological activity; Biological Availability; Cell Membrane Permeability; Chemistry, Medicinal; Dogs; Half-Life; Humans; Life Sciences & Biomedicine; macrocycles; Madin Darby Canine Kidney Cells; Male; metabolism; Microsomes, Liver - metabolism; peptides; Peptides, Cyclic - blood; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacokinetics; Pharmacology & Pharmacy; Protein Structure, Secondary; Rats; Rats, Sprague-Dawley; Science & Technology; Solubility; biological activity; amino acids; FLEXIBILITY; CACO-2; peptides; N-METHYLATION; CELLULAR UPTAKE; DISCOVERY; PASSIVE PERMEABILITY; macrocycles; DRUGS; metabolism; ORAL DELIVERY; INTESTINAL PERMEABILITY
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201600083

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. Down with the func: Thanks to scaffold engineering, cyclic decapeptide 1 exhibits excellent permeability and pharmacokinetic (PK) properties. In this study we investigated further the scope and limitations of this scaffold. The effects of functionalization with polar or charged groups as well as the effect of glycine are discussed. Several cyclic decamers with excellent PK profiles and improved solubilities for such a class of compounds are described.