title: Probing the Physicochemical Boundaries of Cell Permeability and Oral Bioavailability in Lipophilic Macrocycles Inspired by Natural Products.
abstract: Cyclic peptide natural products contain a variety of conserved, nonproteinogenic structural elements such as d-amino acids and amide N-methylation. In addition, many cyclic peptides incorporate γ-amino acids and other elements derived from polyketide synthases. We hypothesized that the position and orientation of these extended backbone elements impact the ADME properties of these hybrid molecules, especially their ability to cross cell membranes and avoid metabolic degradation. Here we report the synthesis of cyclic hexapeptide diastereomers containing γ-amino acids (e.g., statines) and systematically investigate their structure-permeability relationships. These compounds were much more water-soluble and, in many cases, were both more membrane permeable and more stable to liver microsomes than a similar non-statine-containing derivative. Permeability correlated well with the extent of intramolecular hydrogen bonding observed in the solution structures determined in the low-dielectric solvent CDCl3, and one compound showed an oral bioavailability of 21% in rat. Thus, the incorporation of γ-amino acids offers a route to increase backbone diversity and improve ADME properties in cyclic peptide scaffolds.
authors.affiliation: †Department of Chemistry and Biochemistry, University of California-Santa Cruz, 1156 High Street, Santa Cruz, California 95064, United States.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Bockus
authors.affiliation: ‡Department of Pharmaceutical Chemistry, University of California- San Francisco, 1700 4th Street, San Francisco, California 94158, United States.
authors.forename: Katrina W
authors.initials: KW
authors.lastname: Lexa
authors.affiliation: †Department of Chemistry and Biochemistry, University of California-Santa Cruz, 1156 High Street, Santa Cruz, California 95064, United States.
authors.forename: Cameron R
authors.initials: CR
authors.lastname: Pye
authors.affiliation: §Pharmacokinetics and Drug Metabolism, Pfizer Inc., Groton, Connecticut 06340, United States.
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
authors.affiliation: †Department of Chemistry and Biochemistry, University of California-Santa Cruz, 1156 High Street, Santa Cruz, California 95064, United States.
authors.forename: Jarret W
authors.initials: JW
authors.lastname: Gardner
authors.affiliation: †Department of Chemistry and Biochemistry, University of California-Santa Cruz, 1156 High Street, Santa Cruz, California 95064, United States.
authors.forename: Kathryn C R
authors.initials: KC
authors.lastname: Hund
authors.affiliation: †Department of Chemistry and Biochemistry, University of California-Santa Cruz, 1156 High Street, Santa Cruz, California 95064, United States.
authors.forename: William M
authors.initials: WM
authors.lastname: Hewitt
authors.affiliation: †Department of Chemistry and Biochemistry, University of California-Santa Cruz, 1156 High Street, Santa Cruz, California 95064, United States.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Schwochert
authors.affiliation: †Department of Chemistry and Biochemistry, University of California-Santa Cruz, 1156 High Street, Santa Cruz, California 95064, United States.
authors.forename: Emerson
authors.initials: E
authors.lastname: Glassey
authors.affiliation: ∥Worldwide Medicinal Chemistry, Pfizer Inc., Groton, Connecticut 06340, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.affiliation: ∥Worldwide Medicinal Chemistry, Pfizer Inc., Groton, Connecticut 06340, United States.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Mathiowetz
authors.affiliation: ∥Worldwide Medicinal Chemistry, Pfizer Inc., Groton, Connecticut 06340, United States.
authors.forename: Spiros
authors.initials: S
authors.lastname: Liras
authors.affiliation: ‡Department of Pharmaceutical Chemistry, University of California- San Francisco, 1700 4th Street, San Francisco, California 94158, United States.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Jacobson
authors.affiliation: †Department of Chemistry and Biochemistry, University of California-Santa Cruz, 1156 High Street, Santa Cruz, California 95064, United States.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Lokey
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D055598:Chemical Phenomena; D006860:Hydrogen Bonding; D047028:Macrocyclic Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects*; D008958:Models, Molecular; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012997:Solvents / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D001688:Biological Products; D047028:Macrocyclic Compounds; D010456:Peptides, Cyclic; D012997:Solvents