Structure‐activity relationship and metabolic stability studies of backbone cyclization and N‐methylation of melanocortin peptides

Backbone cyclization (BC) and N‐methylation have been shown to enhance the activity and/or selectivity of biologically active peptides and improve metabolic stability and intestinal permeability. In this study, we describe the synthesis, structure‐activity relationship (SAR) and intestinal metabolic stability of a backbone cyclic peptide library, BL3020, based on the linear α‐Melanocyte stimulating hormone analog Phe‐D‐Phe‐Arg‐Trp‐Gly. The drug lead, BL3020‐1, selected from the BL3020 library (compound 1) has been shown to inhibit weight gain in mice following oral administration. Another member of the BL3020 library, BL3020‐17, showed improved biological activity towards the mMC4R, in comparison to BL3020‐1, although neither were selective for MC4R or MC5R. N‐methylation, which restrains conformational freedom while increasing metabolic stability beyond that which is imparted by BC, was used to find analogs with increased selectivity. N‐methylated backbone cyclic libraries were synthesized based on the BL3020 library. SAR studies showed that all the N‐methylated backbone cyclic peptides demonstrated reduced biological activity and selectivity for all the analyzed receptors. N‐methylation of active backbone cyclic peptides destabilized the active conformation or stabilized an inactive conformation, rendering the peptides biologically inactive. N‐methylation of backbone cyclic peptides maintained stability to degradation by intestinal enzymes. © 2008 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 90: 671–682, 2008. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com