On-resin N-methylation of Cyclic Peptides for Discovery of Orally Bioavailable Scaffolds

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2011 Sep 28

PMID 21946276

Citations 100

Authors

Tina R White

Chad M Renzelman

Arthur C Rand

Taha Rezai

Cayla M McEwen

Vladimir M Gelev

Rushia A Turner

Roger G Linington

Siegfried S F Leung

Amit S Kalgutkar

Jonathan N Bauman

Yizhong Zhang

Spiros Liras

David A Price

Alan M Mathiowetz

Matthew P Jacobson

R Scott Lokey

Affiliations

Soon will be listed here.

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.

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