ZevaquenabantZevaquenabant (MRI-1867)

Formula

C₂₅H₂₁ClF₃N₅O₂S

Molar mass

547.11 g·mol⁻¹

CAS

1998760-00-1

PubChem CID

155321421

Origin

A wholly synthetic compound with no natural occurrence. It belongs to academic pharmaceutical research and is not commercialised.

InChIKey

NLXIJZHFEOSWPU-JOCHJYFZSA-N

Editorial estimate, not clinical.

Zevaquenabant, known in the literature under the code MRI-1867, addresses at once the two problems that had buried CB1 receptor antagonists. The first is psychiatric toxicity: rimonabant was withdrawn from the European market in 2008 because blockade of CB1 receptors in the central nervous system provoked anxiety, depression and suicidal ideation. The remedy lies in chemistry: designing a molecule polar enough not to cross the blood-brain barrier, so that only peripheral CB1 receptors are reached. The second problem is efficacy. Fibrosis, the progressive replacement of an organ's functional tissue by scar tissue, engages several redundant pathways, and blocking only one of them rarely produces a sufficient effect. The team of Kunos, Cinar and Iyer at the National Institutes of Health in the United States chose to combine two mechanisms in a single molecule, by grafting onto the CB1 antagonist skeleton a sulfonylated amidine motif that inhibits inducible nitric oxide synthase. The result, reported in murine models of hepatic, pulmonary, renal and cutaneous fibrosis, is an efficacy greater than that of inhibiting each target separately. Work published in 2025 refines the mechanism by designating alveolar macrophages bearing CB1 as the decisive cell population in pulmonary fibrosis. One methodological observation from the skin study deserves to be retained: the cutaneous concentration of the compound proved far lower in ordinary mice than in mice lacking efflux transporters, the induced fibrosis itself increasing the activity of those pumps, which shows that insufficient tissue exposure can be mistaken for an ineffective mechanism.

An entirely chemical route, described here by class only. The molecule is a dihydropyrazole carboximidamide: a dihydropyrazole ring of defined configuration bears a chlorophenyl and a phenyl, and its nitrogen supports a carboximidamide function linked on one side to an aminoethylidene group and on the other to a trifluoromethylphenyl sulfonyl. That last motif, the sulfonylated amidine, is the one that brings inhibition of inducible nitric oxide synthase, while the dihydropyrazole core brings CB1 receptor antagonism.

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 belongs to academic pharmaceutical research and is not commercialised.

Status

Unscheduled

1. 1.Zawatsky et coll. 2021 : le MRI-1867, antagoniste hybride périphérique du CB1 et de l'iNOS, montre une efficacité antifibrotique dans la fibrose cutanée induite par la bléomycinePMID 34650521
2. 2.Basu et coll. 2025 : antagonisme du récepteur CB1 des macrophages alvéolaires profibrotiques dans la fibrose pulmonairePMID 40608428