URB754

Formula

C₁₆H₁₄N₂O₂

Molar mass

266.11 g·mol⁻¹

CAS

86672-58-4

PubChem CID

848487

Origin

A wholly synthetic compound with no natural occurrence. It has never had any use other than in the laboratory, and the activity that had earned it its interest did not belong to it.

InChIKey

GFWNGVKCDGYFKG-UHFFFAOYSA-N

Editorial estimate, not clinical.

URB754 is interesting for what it is not. Published in 2005 in Nature Neuroscience as an inhibitor of monoacylglycerol lipase, arising from the screening of a commercial chemical library, it answered a real need in a field that then lacked tools for manipulating 2-arachidonoylglycerol concentrations. The correction came in two stages. In 2006 Saario and colleagues, at the University of Kuopio, report in Chemistry and Biology that they find no activity: no inhibition of 2-arachidonoylglycerol hydrolysis in rat brain, no inhibition of fatty acid amide hydrolase, no ability to reveal 2-arachidonoylglycerol signalling on sections, where a reference inhibitor succeeds without difficulty. Their conclusion is blunt: the compound cannot serve as a lead structure for developing inhibitors of that enzyme. In 2007 the group that had made the original publication itself identified the cause of the error. Analysis of the commercial lot by chromatography coupled to mass spectrometry and by nuclear magnetic resonance revealed an organomercurial impurity, bis(methylthio)mercurane, whose median inhibitory concentration at the enzyme is 11.9 nanomolar: it was this, and not the benzoxazinone, that carried all the observed activity. The 2005 work was the subject of an erratum published in Nature Neuroscience in 2007. The episode has a general and lasting reach: the apparent potency of a compound arising from a screen on commercial material is worth only as much as the purity of the lot, and attributing an activity to a structure requires that traces have been ruled out.

An entirely chemical route, described here by class only. The molecule is a benzoxazinone: a 3,1-benzoxazin-4-one core bears a methyl on the aromatic ring and an anilino function substituted by a methylphenyl. That skeleton is classically associated with the inhibition of serine hydrolases, which initially made the activity attributed to it plausible.

Sources: EUR-Lex, UNODC, CND, ANSM, IUPHAR/BPS, ChEBI, EUDA. Our method.

Class

ECS modulator (research)

Origin

A wholly synthetic compound with no natural occurrence. It has never had any use other than in the laboratory, and the activity that had earned it its interest did not belong to it.

Status

Unscheduled

1. 1.Saario et coll. 2006 : l'URB754 n'a aucun effet sur l'hydrolyse ni sur la capacité de signalisation du 2-AG dans le cerveau de ratPMID 16931330
2. 2.Tarzia et coll. 2007 : identification d'une impureté bioactive dans un échantillon commercial d'URB754PMID 17970304
3. 3.Makara et coll. 2005 : attribution initiale de l'activité, corrigée par un erratum publié en 2007PMID 16116451