Synthesis of Tic-D-Phe Psi[CH2-CH2] isostere and its use in the development of melanocortin receptor agonists

Xinrong Tian; Xuemei Chen; Lixian Gan; Jeffery C Hayes; Adrian G Switzer; Mark G Solinsky; Frank H Ebetino; John A Wos; Beth B Pinney; Julie A Farmer; Doreen Crossdoersen; Russell J Sheldon

doi:10.1016/j.bmcl.2005.12.005

Synthesis of Tic-D-Phe Psi[CH2-CH2] isostere and its use in the development of melanocortin receptor agonists

Bioorg Med Chem Lett. 2006 Mar 15;16(6):1721-5. doi: 10.1016/j.bmcl.2005.12.005. Epub 2005 Dec 20.

Authors

Xinrong Tian¹, Xuemei Chen, Lixian Gan, Jeffery C Hayes, Adrian G Switzer, Mark G Solinsky, Frank H Ebetino, John A Wos, Beth B Pinney, Julie A Farmer, Doreen Crossdoersen, Russell J Sheldon

Affiliation

¹ Health Care Research Center, Procter & Gamble Pharmaceuticals, 8700 Mason Montgomery Road, Mason, OH 45040, USA. tian.x@pg.com

PMID: 16376076
DOI: 10.1016/j.bmcl.2005.12.005

Abstract

The first synthesis of Tic-D-Phe Psi[CH(2)-CH(2)] isostere is described, which features diastereoselective alkylation of the tricyclic lactam 14. The use of this novel dipeptide isostere in the development of melanocortin agonists has been demonstrated by the synthesis of peptidomimetic 7 and non-peptidic ligand 27. Both compounds displayed significant binding and agonist potency at the MC4R.

MeSH terms

Alkylation
Dipeptides / chemical synthesis*
Dipeptides / chemistry
Dipeptides / metabolism*
Humans
Lactams / chemistry
Ligands
Models, Molecular
Molecular Mimicry
Molecular Structure
Phenylalanine / chemistry*
Receptor, Melanocortin, Type 3 / agonists
Receptor, Melanocortin, Type 4 / agonists*
Stereoisomerism
Structure-Activity Relationship

Substances

Dipeptides
Lactams
Ligands
Receptor, Melanocortin, Type 3
Receptor, Melanocortin, Type 4
Phenylalanine