Journal Article

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

Liras, Spiros, Jacobson, Matthew P, Mathiowetz, Alan M, White, Tina R, Rand, Arthur C, McEwen, Cayla M, Linington, Roger G, Gelev, Vladimir M, Price, David A, Zhang, Yizhong, Renzelman, Chad M, Kalgutkar, Amit S, Lokey, R Scott, Leung, Siegfried S F, Bauman, Jonathan N, Rezai, Taha, Turner, Rushia A

2011

Overview

A single trimethylated species is obtained in an on-resin N-methylation reaction of a cyclic hexapeptide. This regioselectivity is driven by conformation and the presence of intramolecular hydrogen bonds, and is correlated with membrane permeability of the peptides. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/154 / 631/92/606 / 631/92/95 / Animals / Bioavailability / Biochemical Engineering / Biochemistry / Biological Availability / Bioorganic Chemistry / Cell Biology / Chemistry / Chemistry and Materials Science / Chemistry, Pharmaceutical / Chemistry/Food Science / Combinatorial Chemistry Techniques / Computer Simulation / Drug Discovery - methods / Male / Membranes / Methylation / Molecular Structure / Peptides / Peptides, Cyclic - chemistry / Peptides, Cyclic - metabolism / Peptides, Cyclic - pharmacokinetics / Permeability / Physical properties / Rats / Resins / Structure-Activity Relationship