title: Discovery and pharmacological evaluation of growth hormone secretagogue receptor antagonists.
abstract: 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.
authors.affiliation: Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6098, USA. zhili.xin@abbott.com
authors.forename: Zhili
authors.initials: Z
authors.lastname: Xin
authors.forename: Michael D
authors.initials: MD
authors.lastname: Serby
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.forename: Christi
authors.initials: C
authors.lastname: Kosogof
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Szczepankiewicz
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.forename: Charles W
authors.initials: CW
authors.lastname: Hutchins
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Sarris
authors.forename: Ethan D
authors.initials: ED
authors.lastname: Hoff
authors.forename: H Douglas
authors.initials: HD
authors.lastname: Falls
authors.forename: Chun W
authors.initials: CW
authors.lastname: Lin
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ogiela
authors.forename: Christine A
authors.initials: CA
authors.lastname: Collins
authors.forename: Michael E
authors.initials: ME
authors.lastname: Brune
authors.forename: Eugene N
authors.initials: EN
authors.lastname: Bush
authors.forename: Brian A
authors.initials: BA
authors.lastname: Droz
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Fey
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Knourek-Segel
authors.forename: Robin
authors.initials: R
authors.lastname: Shapiro
authors.forename: Peer B
authors.initials: PB
authors.lastname: Jacobson
authors.forename: David W A
authors.initials: DW
authors.lastname: Beno
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Turner
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
mesh_terms: 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
chemical_list: D000577:Amides; D000631:Aminopyridines; D019440:Anti-Obesity Agents; D001067:Appetite Depressants; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D014508:Urea