title: Diaryl urea analogues of SB-334867 as orexin-1 receptor antagonists.
abstract: As a part of our program to develop OX1-CB1 bivalent ligands, we required a better understanding of the basic structure-activity relationships (SARs) of orexin antagonists. A series of SB-334867 analogues were synthesized and evaluated in calcium mobilization assays. SAR results suggest that the 2-methylbenzoxazole moiety may be replaced with a disubstituted 4-aminophenyl group without loss of activity and an electron-deficient system is generally preferred at the 1,5-naphthyridine moiety for OX1 antagonist activity. In particular, substitution of larger potential linkers such as n-hexyl provided compound 33 with equivalent activity at the OX1 receptor compared to the lead compound SB-334867. These compounds should be of value in the development of ligands targeting the orexin-1 receptor and its potential heterodimers.
authors.affiliation: Research Triangle Institute, 3040 Cornwallis Road, Research Triangle Park, NC 27709, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Perrey
authors.forename: Brian P
authors.initials: BP
authors.lastname: Gilmour
authors.forename: Scott P
authors.initials: SP
authors.lastname: Runyon
authors.forename: Brian F
authors.initials: BF
authors.lastname: Thomas
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D001583:Benzoxazoles / Q000737:chemistry / Q000494:pharmacology*; D016503:Drug Delivery Systems; D008024:Ligands; D015394:Molecular Structure; D009287:Naphthyridines; D064446:Orexin Receptors; D011485:Protein Binding / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D018013:Receptors, Neuropeptide / Q000819:agonists*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D008024:Ligands; D009287:Naphthyridines; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D014508:Urea