2,4-diaminopyrimidine derivatives as potent growth hormone secretagogue receptor antagonists.
Ghrelin, a gut-derived orexigenic hormone, is an endogenous ligand of the growth hormone secretagogue receptor (GHS-R). Centrally administered ghrelin has been shown to cause hunger and increase food intake in rodents. Inhibition of ghrelin actions with ghrelin antibody, peptidyl GHS-R antagonists, and antisense oligonucleosides resulted in weight loss and food intake decrease in rodents. Here we report the effects of GHS-R antagonists, some of which were potent, selective, and orally bioavailable. A structure-activity relationship study led to the discovery of 8a, which was effective in decreasing food intake and body weight in several acute rat studies.
Serby
Michael D
MD
Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6098, USA. michael.serby@abbott.com
Zhao
Hongyu
H
Szczepankiewicz
Bruce G
BG
Kosogof
Christi
C
Xin
Zhili
Z
Liu
Bo
B
Liu
Mei
M
Nelson
Lissa T J
LT
Kaszubska
Wiweka
W
Falls
H Douglas
HD
Schaefer
Verlyn
V
Bush
Eugene N
EN
Shapiro
Robin
R
Droz
Brian A
BA
Knourek-Segel
Victoria E
VE
Fey
Thomas A
TA
Brune
Michael E
ME
Beno
David W A
DW
Turner
Theresa M
TM
Collins
Christine A
CA
Jacobson
Peer B
PB
Sham
Hing L
HL
Liu
Gang
G
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D054440:Receptors, Ghrelin; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors
D008024:Ligands; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; C017205:2,4-diaminopyrimidine