Synthesis of Tic-D-Phe Psi[CH2-CH2] isostere and its use in the development of melanocortin receptor agonists.
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.
Tian
Xinrong
X
Health Care Research Center, Procter & Gamble Pharmaceuticals, 8700 Mason Montgomery Road, Mason, OH 45040, USA. tian.x@pg.com
Chen
Xuemei
X
Gan
Lixian
L
Hayes
Jeffery C
JC
Switzer
Adrian G
AG
Solinsky
Mark G
MG
Ebetino
Frank H
FH
Wos
John A
JA
Pinney
Beth B
BB
Farmer
Julie A
JA
Crossdoersen
Doreen
D
Sheldon
Russell J
RJ
D000478:Alkylation; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007769:Lactams / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D010649:Phenylalanine / Q000737:chemistry*; D044104:Receptor, Melanocortin, Type 3 / Q000819:agonists; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004151:Dipeptides; D007769:Lactams; D008024:Ligands; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D010649:Phenylalanine