title: Hydrolytic instability of the important orexin 1 receptor antagonist SB-334867: possible confounding effects on in vivo and in vitro studies.
abstract: SB-334867 has been an important ligand for the study of the orexin 1 (OX1) receptor due to its high OX1/OX2 selectivity and bioavailability. This ligand however, contains a 2-methylbenzoxazole ring system which is known to undergo hydrolysis, particularly under acidic or basic conditions. The possibility that SB-334867 would be susceptible to significant hydrolysis was evaluated in various formulations and in the solid state. SB-334867 was found to be unstable under conditions commonly employed to prepare stock solutions for in vitro and in vivo studies. In addition, and most alarmingly, the hydrochloride salt of SB-334867 was found to quantitatively decompose to an OX1-inactive product even in the solid state. These findings combine to suggest that studies using SB-334867 (and any other 2-methylbenzoxazole-containing compound) should be performed with great care to avoid the confounding effects of the rapid hydrolytic decomposition of this susceptible structure.
authors.affiliation: Research Triangle Institute, 3040 Cornwallis Road, Research Triangle Park, NC 27709, USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: McElhinny
authors.forename: Anita H
authors.initials: AH
authors.lastname: Lewin
authors.forename: S Wayne
authors.initials: SW
authors.lastname: Mascarella
authors.forename: Scott
authors.initials: S
authors.lastname: Runyon
authors.forename: Lawrence
authors.initials: L
authors.lastname: Brieaddy
authors.forename: F Ivy
authors.initials: FI
authors.lastname: Carroll
mesh_terms: D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry*; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008024:Ligands; D015394:Molecular Structure; D009287:Naphthyridines; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry
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