Synthesis of 2,4,5-trisubstituted tetrahydropyrans as peptidomimetic scaffolds for melanocortin receptor ligands.
[reaction: see text] We have synthesized a series of 2,4,5-trisubstituted tetrahydropyran derivatives to determine the utility of this scaffold as a peptidomimetic platform. The key synthetic steps involved a palladium-mediated cross-coupling reaction of a dihydropyran-4-one moiety to introduce R(2) followed by a sequential regio- and diastereoselective reduction of sp(2) carbon centers. Selected compounds have shown biological activity at melanocortin receptors, indicating that this scaffold may be useful in the design of peptidomimetics relating to a tripeptide structure.
Kulesza
Anna
A
Procter and Gamble Pharmaceuticals, Health Care Research Center, Mason, Ohio 45040, USA.
Ebetino
Frank H
FH
Mishra
Rajesh K
RK
Cross-Doersen
Doreen
D
Mazur
Adam W
AW
D040761:Biomimetic Materials; D008024:Ligands; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry*; D010084:Oxidation-Reduction; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018043:Receptors, Corticotropin / Q000378:metabolism*; D044101:Receptors, Melanocortin; D013237:Stereoisomerism
D008024:Ligands; D009842:Oligopeptides; D011714:Pyrans; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin