Design and Development of a Cyclic Decapeptide Scaffold with Suitable Properties for Bioavailability and Oral Exposure. (6th May 2016)

• Record Type: Journal Article
• Authors: Fouché, Marianne; Schäfer, Michael; Berghausen, Jörg; Desrayaud, Sandrine; Blatter, Markus; Piéchon, Philippe; Dix, Ina; Martin Garcia, Aimar; Roth, Hans‐Jörg
• Is Part Of: ChemMedChem. Volume 11:Number 10(2016)
• Page Start: 1048
• Page End: 1059
• Publication Date: 2016-05-06
• Subjects: macrocycles -- NMR spectroscopy -- peptides -- permeability -- pharmacokinetics; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201600082
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Permeability and oral bioavailability of macrocyclic peptides still represent difficult challenges in drug discovery. Despite the recognized potential of macrocyclic peptides as therapeutics, their use is still restricted to extracellular targets and intravenous administration. Indeed, macrocyclic peptides generally suffer from limited proteolytic stability, high clearance, and poor membrane permeability, and this leads to the absence of systemic exposure after oral administration. To overcome these limitations, we started to investigate the development of a general cyclic decapeptide scaffold that possesses ideal features for cell permeability and oral exposure. On the basis of a rigid hairpin structure, the scaffold design aimed to decrease the overall polarity of the compound, thereby limiting the energetic cost of NH desolvation and the entropy penalty during cell penetration. The results of this study also demonstrate the importance of rigidity for the β‐turn design regarding clearance. To stabilize the scaffold in the desired β‐hairpin conformation, the introduction ofd ‐proline at the i +1 turn position proved to be beneficial for both permeability and clearance. As a result, cyclopeptide decamers with unprecedented high values for oral bioavailability and exposure are reported herein. NMR spectroscopy conformation and dynamic analysis confirmed, for selected examples, the rigidity of the scaffold and the presence of transannular hydrogen bonds in polar and apolar environments. Furthermore, we showed, for one compound, that its transition from a polar environment to an apolar one was accompanied by an increased molecular motion, revealing an entropy contribution to membrane permeation. Abstract : Status: available ! A generic decapeptide scaffold designed to exhibit good properties for permeability and oral exposure is reported. Cyclic peptides are shown to display a conformation that is ideal for cell permeation if coupled to the right NMe amide pattern. According to NMR spectroscopy, compound8, which displays excellent bioavailability, shows surprisingly higher conformational flexibility in apolar solvents than in polar solvents, indicative of an entropic contribution to permeability.