Zevaquenabant

{{Short description|Chemical compound}}

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| legal_status = Investigational

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| synonyms = S-MRI-1867; INV-101; MRI-1867

| CAS_number = 1998760-00-1

| UNII = T7JYL5VB4H

| PubChem = 155321421

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| IUPAC_name = (4S)-N-(1-Aminoethylidene)-5-(4-chlorophenyl)-4-phenyl-{{prime|N}}-[4-(trifluoromethyl)phenyl]sulfonyl-3,4-dihydropyrazole-2-carboximidamide

| C = 25 | H = 21 | Cl = 1 | F = 3 | N = 5 | O = 2 | S = 1

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Zevaquenabant (S-MRI-1867, INV-101, or MRI-1867) is an investigational small-molecule drug, discovered by Dr George Kunos, Dr Resat Cinar, and Dr Malliga iyer at the National Institutes of Health. Zevaquenabant was described as a third generation cannabinoid receptor 1 (CB1R) antagonist due to its peripheral selectivity and polypharmacology.{{cite journal |last1=Cinar |first1=R |last2=Iyer |first2=MR |last3=Kunos |first3=G |title=The therapeutic potential of second and third generation CB(1)R antagonists. |journal=Pharmacology & Therapeutics |date=April 2020 |volume=208 |pages=107477 |doi=10.1016/j.pharmthera.2020.107477 |pmid=31926199 |pmc=8605822 }} It acts as a peripherally selective inverse agonist of the cannabinoid receptor 1 and an inducible nitric oxide synthase (iNOS) inhibitor.{{cite journal |last1=Cinar |first1=Resat |last2=Iyer |first2=Malliga R. |last3=Liu |first3=Ziyi |last4=Cao |first4=Zongxian |last5=Jourdan |first5=Tony |last6=Erdelyi |first6=Katalin |last7=Godlewski |first7=Grzegorz |last8=Szanda |first8=Gergő |last9=Liu |first9=Jie |last10=Park |first10=Joshua K. |last11=Mukhopadhyay |first11=Bani |last12=Rosenberg |first12=Avi Z. |last13=Lieow |first13=Jeih-San |last14=Lorenz |first14=Robin G. |last15=Pacher |first15=Pal |last16=Innis |first16=Robert B. |last17=Kunos |first17=George |title=Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis |journal=JCI Insight |date=21 July 2016 |volume=1 |issue=11 |doi=10.1172/jci.insight.87336 |pmid=27525312 |pmc=4979564 |url=https://insight.jci.org/articles/view/87336}}{{cite journal |last1=Iyer |first1=Malliga R. |last2=Cinar |first2=Resat |last3=Coffey |first3=Nathan J. |last4=Kunos |first4=George |title=Synthesis of 13 C 6 -labeled, dual-target inhibitor of cannabinoid-1 receptor (CB 1 R) and inducible nitric oxide synthase (iNOS) |journal=Journal of Labelled Compounds and Radiopharmaceuticals |date=August 2018 |volume=61 |issue=10 |pages=773–779 |doi=10.1002/jlcr.3639|pmid=29790591 |s2cid=46895177 }} It has been studied in the experimental models of fibrotic disorders such as liver fibrosis^[1], chronic kidney disease,{{cite journal |last1=Udi |first1=Shiran |last2=Hinden |first2=Liad |last3=Ahmad |first3=Majdoleen |last4=Drori |first4=Adi |last5=Iyer |first5=Malliga R. |last6=Cinar |first6=Resat |last7=Herman-Edelstein |first7=Michal |last8=Tam |first8=Joseph |title=Dual inhibition of cannabinoid CB 1 receptor and inducible NOS attenuates obesity-induced chronic kidney disease |journal=British Journal of Pharmacology |date=January 2020 |volume=177 |issue=1 |pages=110–127 |doi=10.1111/bph.14849|pmid=31454063 |pmc=6976880 }} idiopathic pulmonary fibrosis,{{cite journal |last1=Cinar |first1=Resat |last2=Gochuico |first2=Bernadette R. |last3=Iyer |first3=Malliga R. |last4=Jourdan |first4=Tony |last5=Yokoyama |first5=Tadafumi |last6=Park |first6=Joshua K. |last7=Coffey |first7=Nathan J. |last8=Pri-Chen |first8=Hadass |last9=Szanda |first9=Gergő |last10=Liu |first10=Ziyi |last11=Mackie |first11=Ken |last12=Gahl |first12=William A. |last13=Kunos |first13=George |title=Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis |journal=JCI Insight |date=20 April 2017 |volume=2 |issue=8 |doi=10.1172/jci.insight.92281 |pmid=28422760 |pmc=5396529 |url=https://insight.jci.org/articles/view/92281}} Hermansky-Pudlak syndrome pulmonary fibrosis,{{cite journal |last1=Padilha |first1=Elias C. |last2=Yang |first2=Mengbi |last3=Shah |first3=Pranav |last4=Wang |first4=Amy Q. |last5=Duan |first5=Jianmin |last6=Park |first6=Joshua K. |last7=Zawatsky |first7=Charles N. |last8=Malicdan |first8=May Christine V. |last9=Kunos |first9=George |last10=Iyer |first10=Malliga R. |last11=Gaucher |first11=Geneviève |last12=Ravenelle |first12=François |last13=Cinar |first13=Resat |last14=Xu |first14=Xin |title=In vitro and in vivo pharmacokinetic characterization, chiral conversion and PBPK scaling towards human PK simulation of S-MRI-1867, a drug candidate for Hermansky-Pudlak syndrome pulmonary fibrosis |journal=Biomedicine & Pharmacotherapy |date=December 2023 |volume=168 |pages=115178 |doi=10.1016/j.biopha.2023.115178|pmid=37890204 |s2cid=264505730 |doi-access=free |pmc=10715448 }}{{cite journal |last1=Cinar |first1=R |last2=Park |first2=JK |last3=Zawatsky |first3=CN |last4=Coffey |first4=NJ |last5=Bodine |first5=SP |last6=Abdalla |first6=J |last7=Yokoyama |first7=T |last8=Jourdan |first8=T |last9=Jay |first9=L |last10=Zuo |first10=MXG |last11=O'Brien |first11=KJ |last12=Huang |first12=J |last13=Mackie |first13=K |last14=Alimardanov |first14=A |last15=Iyer |first15=MR |last16=Gahl |first16=WA |last17=Kunos |first17=G |last18=Gochuico |first18=BR |last19=Malicdan |first19=MCV |title=CB(1) R and iNOS are distinct players promoting pulmonary fibrosis in Hermansky-Pudlak syndrome. |journal=Clinical and Translational Medicine |date=July 2021 |volume=11 |issue=7 |pages=e471 |doi=10.1002/ctm2.471 |pmid=34323400 |pmc=8255071 }} skin fibrosis,{{cite journal |last1=Zawatsky |first1=CN |last2=Park |first2=JK |last3=Abdalla |first3=J |last4=Kunos |first4=G |last5=Iyer |first5=MR |last6=Cinar |first6=R |title=Peripheral Hybrid CB(1)R and iNOS Antagonist MRI-1867 Displays Anti-Fibrotic Efficacy in Bleomycin-Induced Skin Fibrosis. |journal=Frontiers in Endocrinology |date=2021 |volume=12 |pages=744857 |doi=10.3389/fendo.2021.744857 |doi-access=free |pmid=34650521 |pmc=8505776 }} and metabolic disorders such as obesity^[2] and dyslipidemia.{{cite journal |last1=Roger |first1=Célia |last2=Buch |first2=Chloé |last3=Muller |first3=Tania |last4=Leemput |first4=Julia |last5=Demizieux |first5=Laurent |last6=Passilly-Degrace |first6=Patricia |last7=Cinar |first7=Resat |last8=Iyer |first8=Malliga R. |last9=Kunos |first9=George |last10=Vergès |first10=Bruno |last11=Degrace |first11=Pascal |last12=Jourdan |first12=Tony |title=Simultaneous Inhibition of Peripheral CB1R and iNOS Mitigates Obesity-Related Dyslipidemia Through Distinct Mechanisms |journal=Diabetes |date=1 October 2020 |volume=69 |issue=10 |pages=2120–2132 |doi=10.2337/db20-0078|pmid=32680936 |pmc=7506827 }}