On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds
| Autor: | 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 SF, Kalgutkar, Amit S, Bauman, Jonathan N, Zhang, Yizhong, Liras, Spiros, Price, David A, Mathiowetz, Alan M, Jacobson, Matthew P, Lokey, R Scott |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Cyclic Biochemistry & Molecular Biology Molecular Structure Biological Availability Methylation Rats Structure-Activity Relationship Chemistry Medicinal and Biomolecular Chemistry Pharmaceutical Drug Discovery Animals Combinatorial Chemistry Techniques Computer Simulation Biochemistry and Cell Biology Peptides |
| Zdroj: | Nature chemical biology, vol 7, iss 11 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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