title: On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds.
abstract: Backbone N-methylation is common among peptide natural products and has a substantial impact on both the physical properties and the conformational states of cyclic peptides. However, the specific impact of N-methylation on passive membrane diffusion in cyclic peptides has not been investigated systematically. Here we report a method for the selective, on-resin N-methylation of cyclic peptides to generate compounds with drug-like membrane permeability and oral bioavailability. The selectivity and degree of N-methylation of the cyclic peptide was dependent on backbone stereochemistry, suggesting that conformation dictates the regiochemistry of the N-methylation reaction. The permeabilities of the N-methyl variants were corroborated by computational studies on a 1,024-member virtual library of N-methyl cyclic peptides. One of the most permeable compounds, a cyclic hexapeptide (molecular mass = 755 Da) with three N-methyl groups, showed an oral bioavailability of 28% in rat.
authors.affiliation: Department of Chemistry, University of California Santa Cruz, Santa Cruz, California, USA.
authors.forename: Tina R
authors.initials: TR
authors.lastname: White
authors.forename: Chad M
authors.initials: CM
authors.lastname: Renzelman
authors.forename: Arthur C
authors.initials: AC
authors.lastname: Rand
authors.forename: Taha
authors.initials: T
authors.lastname: Rezai
authors.forename: Cayla M
authors.initials: CM
authors.lastname: McEwen
authors.forename: Vladimir M
authors.initials: VM
authors.lastname: Gelev
authors.forename: Rushia A
authors.initials: RA
authors.lastname: Turner
authors.forename: Roger G
authors.initials: RG
authors.lastname: Linington
authors.forename: Siegfried S F
authors.initials: SS
authors.lastname: Leung
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Bauman
authors.forename: Yizhong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Spiros
authors.initials: S
authors.lastname: Liras
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Alan M
authors.initials: AM
authors.lastname: Mathiowetz
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Jacobson
authors.forename: R Scott
authors.initials: RS
authors.lastname: Lokey
mesh_terms: D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D020650:Combinatorial Chemistry Techniques; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods; D008297:Male; D008745:Methylation; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D010456:Peptides, Cyclic