title: 2,4-diaminopyrimidine derivatives as potent growth hormone secretagogue receptor antagonists.
abstract: 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.
authors.affiliation: Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6098, USA. michael.serby@abbott.com
authors.forename: Michael D
authors.initials: MD
authors.lastname: Serby
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Szczepankiewicz
authors.forename: Christi
authors.initials: C
authors.lastname: Kosogof
authors.forename: Zhili
authors.initials: Z
authors.lastname: Xin
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.forename: Lissa T J
authors.initials: LT
authors.lastname: Nelson
authors.forename: Wiweka
authors.initials: W
authors.lastname: Kaszubska
authors.forename: H Douglas
authors.initials: HD
authors.lastname: Falls
authors.forename: Verlyn
authors.initials: V
authors.lastname: Schaefer
authors.forename: Eugene N
authors.initials: EN
authors.lastname: Bush
authors.forename: Robin
authors.initials: R
authors.lastname: Shapiro
authors.forename: Brian A
authors.initials: BA
authors.lastname: Droz
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Knourek-Segel
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Fey
authors.forename: Michael E
authors.initials: ME
authors.lastname: Brune
authors.forename: David W A
authors.initials: DW
authors.lastname: Beno
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Turner
authors.forename: Christine A
authors.initials: CA
authors.lastname: Collins
authors.forename: Peer B
authors.initials: PB
authors.lastname: Jacobson
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
mesh_terms: 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
chemical_list: D008024:Ligands; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; C017205:2,4-diaminopyrimidine