Discovery and pharmacological evaluation of growth hormone secretagogue receptor antagonists.
The discovery and pharmacological evaluation of potent, selective, and orally bioavailable growth hormone secretagogue receptor (GHS-R) antagonists are reported. Previously, 2,4-diaminopyrimidine-based GHS-R antagonists reported from our laboratories have been shown to be dihydrofolate reductase (DHFR) inhibitors. By comparing the X-ray crystal structure of DHFR docked with our GHS-R antagonists and GHS-R modeling, we designed and synthesized a series of potent and DHFR selective GHS-R antagonists with good pharmacokinetic (PK) profiles. An amide derivative 13d (Ca2+ flux IC50 = 188 nM, [brain]/[plasma] = 0.97 @ 8 h in rat) showed a 10% decrease in 24 h food intake in rats, and over 5% body weight reduction after 14-day oral treatment in diet-induced obese (DIO) mice. In comparison, a urea derivative 14c (Ca2+ flux IC50 = 7 nM, [brain]/[plasma] = 0.0 in DIO) failed to show significant effect on food intake in the acute feeding DIO model. These observations demonstrated for the first time that peripheral GHS-R blockage with small molecule GHS-R antagonists might not be sufficient for suppressing appetite and inducing body weight reduction.
Xin
Zhili
Z
Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6098, USA. zhili.xin@abbott.com
Serby
Michael D
MD
Zhao
Hongyu
H
Kosogof
Christi
C
Szczepankiewicz
Bruce G
BG
Liu
Mei
M
Liu
Bo
B
Hutchins
Charles W
CW
Sarris
Kathy A
KA
Hoff
Ethan D
ED
Falls
H Douglas
HD
Lin
Chun W
CW
Ogiela
Christopher A
CA
Collins
Christine A
CA
Brune
Michael E
ME
Bush
Eugene N
EN
Droz
Brian A
BA
Fey
Thomas A
TA
Knourek-Segel
Victoria E
VE
Shapiro
Robin
R
Jacobson
Peer B
PB
Beno
David W A
DW
Turner
Teresa M
TM
Sham
Hing L
HL
Liu
Gang
G
D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001067:Appetite Depressants / Q000138:chemical synthesis / Q000494:pharmacology; D001682:Biological Availability; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D018360:Crystallography, X-Ray; D004435:Eating / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D054440:Receptors, Ghrelin; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology
D000577:Amides; D000631:Aminopyridines; D019440:Anti-Obesity Agents; D001067:Appetite Depressants; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D014508:Urea