On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds.

Research paper by Tina R TR White, Chad M CM Renzelman, Arthur C AC Rand, Taha T Rezai, Cayla M CM McEwen, Vladimir M VM Gelev, Rushia A RA Turner, Roger G RG Linington, Siegfried S F SS Leung, Amit S AS Kalgutkar, Jonathan N JN Bauman, Yizhong Y Zhang, Spiros S Liras, David A DA Price, Alan M AM Mathiowetz, et al.

Indexed on: 29 Sep '11Published on: 29 Sep '11Published in: Nature Chemical Biology


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.