Spiro(indoline-3,4'-piperidine) growth hormone secretagogues as ghrelin mimetics.
A series of small molecules derived from MK-0677, a potent synthetic GHS, mimicking the N-terminal Gly-Ser-O-(n-octanoyl)-L-Ser-Phe segment of ghrelin was synthesized and tested in a binding and in a functional assay measuring intracellular calcium elevation in HEK-293 cells expressing hGHSR1a. Replacement of Phe in this tetrapeptide with a spiro(indoline-3,4'-piperidine) group, Gly-Ser with 2-aminoisobutyric acid, and O-(n-octanoyl)-L-Ser with O-benzyl-D-Ser provided synthetic GHS agonists with similar functional potency as ghrelin.
Palucki
B L
BL
Department of Medicinal Chemistry, Merck Research Laboratories, 07065, Rahway, NJ, USA. brenda_palucki@merck.com
Feighner
S D
SD
Pong
S
S
McKee
K K
KK
Hreniuk
D L
DL
Tan
C
C
Howard
A D
AD
Van der Ploeg
L H
LH
Patchett
A A
AA
Nargund
R P
RP
D001665:Binding Sites / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D054439:Ghrelin; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D049449:Luminescence; D018716:Molecular Mimicry; D036361:Peptide Hormones; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D010880:Piperidines / Q000138:chemical synthesis / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D013141:Spiro Compounds / Q000737:chemistry / Q000378:metabolism*
D054439:Ghrelin; D007211:Indoles; D036361:Peptide Hormones; D010455:Peptides; D010880:Piperidines; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D013141:Spiro Compounds; C032727:piperidine; C094817:ibutamoren mesylate; D002118:Calcium