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- Title
On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds.
- Authors
White, Tina R; Renzelman, Chad M; Rand, Arthur C; Rezai, Taha; McEwen, Cayla M; Gelev, Vladimir M; Turner, Rushia A; Linington, Roger G; Leung, Siegfried S F; Kalgutkar, Amit S; Bauman, Jonathan N; Zhang, Yizhong; Liras, Spiros; Price, David A; Mathiowetz, Alan M; Jacobson, Matthew P; Lokey, R Scott
- 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.
- Publication
Nature chemical biology, 2011, Vol 7, Issue 11, p810
- ISSN
1552-4469
- Publication type
Journal Article
- DOI
10.1038/nchembio.664