title: Design and Development of a Cyclic Decapeptide Scaffold with Suitable Properties for Bioavailability and Oral Exposure.
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 of d-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.
authors.affiliation: Global Discovery Chemistry/Macrocycles, Novartis Institute for BioMedical Research, Basel, 4002, Switzerland. marianne.fouche@novartis.com.
authors.forename: Marianne
authors.identifier: http://orcid.org/0000-0001-6536-679X
authors.initials: M
authors.lastname: Fouché
authors.affiliation: Global Discovery Chemistry/CADD, Novartis Institute for BioMedical Research, Basel, 4002, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfer
authors.affiliation: Metabolism and Pharmacokinetics, Novartis Institute for BioMedical Research, Basel, 4002, Switzerland.
authors.forename: Jörg
authors.initials: J
authors.lastname: Berghausen
authors.affiliation: Metabolism and Pharmacokinetics, Novartis Institute for BioMedical Research, Basel, 4002, Switzerland.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Desrayaud
authors.affiliation: Global Discovery Chemistry/Analytics (NMR), Novartis Institute for BioMedical Research, Basel, 4002, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Blatter
authors.affiliation: Global Discovery Chemistry/Analytics (Crystallography), Novartis Institute for BioMedical Research, Basel, 4002, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Piéchon
authors.affiliation: Global Discovery Chemistry/Analytics (Crystallography), Novartis Institute for BioMedical Research, Basel, 4002, Switzerland.
authors.forename: Ina
authors.initials: I
authors.lastname: Dix
authors.affiliation: The University of the Basque Country-Euskal Herriko Unibertsitatea, Campus de Leioa, 48949, Leioa, Spain.
authors.forename: Aimar
authors.initials: A
authors.lastname: Martin Garcia
authors.affiliation: Global Discovery Chemistry/Macrocycles, Novartis Institute for BioMedical Research, Basel, 4002, Switzerland.
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Roth
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D006207:Half-Life; D006860:Hydrogen Bonding; D061985:Madin Darby Canine Kidney Cells; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D010456:Peptides, Cyclic
keywords: NMR spectroscopy; macrocycles; peptides; permeability; pharmacokinetics