Novel tetrahydropyran-based peptidomimetics from a bioisosteric transformation of a tripeptide. Evidence of their activity at melanocortin receptors.
We have prepared novel peptidomimetics based on a 2,4,6-trisubstituted tetrahydropyran. This scaffold was constructed in an isosteric transformation using conceptual constraints imposed on a tripeptide moiety involving O(i)'-C(i+1)(gamma) and O(i)'-N(i+2) formal cyclization modes. A series of regioselective transformations commencing with a substituted dihydropyran-4-one readily provided the required analogues. Specific tetrahydropyrane analogues modeled on PheArgTrp as a truncated version of the melanocortin receptor message sequence, showed activity at the melanocortin receptors MC4R and MC1R. Thus, the 2,4,6-trisubstituted tetrahydropyran scaffold has provided a potentially useful peptidomimetic lead, and conceptual cyclization of peptide moieties can offer a valuable design strategy in peptidomimetic research.
Mazur
Adam W
AW
Procter & Gamble Pharmaceuticals, Health Care Research Center, Mason, OH 45040, USA. amazur@cinci.rr.com
Kulesza
Anna
A
Mishra
Rajesh K
RK
Cross-Doersen
Doreen
D
Russell
Anne F
AF
Ebetino
Frank H
FH
D001120:Arginine / Q000737:chemistry; D040761:Biomimetic Materials; D002478:Cells, Cultured; D006801:Humans; D007536:Isomerism; D008956:Models, Chemical; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism; D010649:Phenylalanine / Q000737:chemistry; D011485:Protein Binding; D011714:Pyrans / Q000737:chemistry* / Q000494:pharmacology; D044101:Receptors, Melanocortin / Q000187:drug effects* / Q000235:genetics; D014364:Tryptophan / Q000737:chemistry
D009842:Oligopeptides; D010456:Peptides, Cyclic; D011714:Pyrans; D044101:Receptors, Melanocortin; D010649:Phenylalanine; D014364:Tryptophan; D001120:Arginine