Zevaquenabant Explained

Legal Status:Investigational
Synonyms:S-MRI-1867; INV-101; MRI-1867
Cas Number:1998760-00-1
Unii:T7JYL5VB4H
Pubchem:155321421
Iupac Name:(4S)-N-(1-Aminoethylidene)-5-(4-chlorophenyl)-4-phenyl--[4-(trifluoromethyl)phenyl]sulfonyl-3,4-dihydropyrazole-2-carboximidamide
C:25
H:21
Cl:1
F:3
N:5
O:2
S:1

Zevaquenabant (S-MRI-1867, INV-101, or MRI-1867) is an investigational small-molecule drug, discovered by the National Institutes of Health. Zevaquenabant was described as a third generation cannabinoid receptor 1 (CB1R) antagonist due to its peripheral selectivity and polypharmacology.[1] It acts as a peripherally selective inverse agonist of the cannabinoid receptor 1 and an inducible nitric oxide synthase (iNOS) inhibitor.[2] [3] It has been studied in the experimental models of fibrotic disorders such as liver fibrosis[1], chronic kidney disease,[4] idiopathic pulmonary fibrosis,[5] Hermansky-Pudlak syndrome pulmonary fibrosis,[6] [7] skin fibrosis,[8] and metabolic disorders such as obesity[2] and dyslipidemia.[9]

Notes and References

  1. Cinar . R . Iyer . MR . Kunos . G . The therapeutic potential of second and third generation CB(1)R antagonists. . Pharmacology & Therapeutics . April 2020 . 208 . 107477 . 10.1016/j.pharmthera.2020.107477 . 31926199 . 8605822 .
  2. Cinar . Resat . Iyer . Malliga R. . Liu . Ziyi . Cao . Zongxian . Jourdan . Tony . Erdelyi . Katalin . Godlewski . Grzegorz . Szanda . Gergő . Liu . Jie . Park . Joshua K. . Mukhopadhyay . Bani . Rosenberg . Avi Z. . Lieow . Jeih-San . Lorenz . Robin G. . Pacher . Pal . Innis . Robert B. . Kunos . George . Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis . JCI Insight . 21 July 2016 . 1 . 11 . 10.1172/jci.insight.87336 . 27525312 . 4979564 .
  3. Iyer . Malliga R. . Cinar . Resat . Coffey . Nathan J. . Kunos . George . Synthesis of 13 C 6 -labeled, dual-target inhibitor of cannabinoid-1 receptor (CB 1 R) and inducible nitric oxide synthase (iNOS) . Journal of Labelled Compounds and Radiopharmaceuticals . August 2018 . 61 . 10 . 773–779 . 10.1002/jlcr.3639. 29790591 . 46895177 .
  4. Udi . Shiran . Hinden . Liad . Ahmad . Majdoleen . Drori . Adi . Iyer . Malliga R. . Cinar . Resat . Herman-Edelstein . Michal . Tam . Joseph . Dual inhibition of cannabinoid CB 1 receptor and inducible NOS attenuates obesity-induced chronic kidney disease . British Journal of Pharmacology . January 2020 . 177 . 1 . 110–127 . 10.1111/bph.14849. 31454063 . 6976880 .
  5. Cinar . Resat . Gochuico . Bernadette R. . Iyer . Malliga R. . Jourdan . Tony . Yokoyama . Tadafumi . Park . Joshua K. . Coffey . Nathan J. . Pri-Chen . Hadass . Szanda . Gergő . Liu . Ziyi . Mackie . Ken . Gahl . William A. . Kunos . George . Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis . JCI Insight . 20 April 2017 . 2 . 8 . 10.1172/jci.insight.92281 . 28422760 . 5396529 .
  6. Padilha . Elias C. . Yang . Mengbi . Shah . Pranav . Wang . Amy Q. . Duan . Jianmin . Park . Joshua K. . Zawatsky . Charles N. . Malicdan . May Christine V. . Kunos . George . Iyer . Malliga R. . Gaucher . Geneviève . Ravenelle . François . Cinar . Resat . Xu . Xin . 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 . Biomedicine & Pharmacotherapy . December 2023 . 168 . 115178 . 10.1016/j.biopha.2023.115178. 37890204 . 264505730 . free . 10715448 .
  7. Cinar . R . Park . JK . Zawatsky . CN . Coffey . NJ . Bodine . SP . Abdalla . J . Yokoyama . T . Jourdan . T . Jay . L . Zuo . MXG . O'Brien . KJ . Huang . J . Mackie . K . Alimardanov . A . Iyer . MR . Gahl . WA . Kunos . G . Gochuico . BR . Malicdan . MCV . CB(1) R and iNOS are distinct players promoting pulmonary fibrosis in Hermansky-Pudlak syndrome. . Clinical and Translational Medicine . July 2021 . 11 . 7 . e471 . 10.1002/ctm2.471 . 34323400 . 8255071 .
  8. Zawatsky . CN . Park . JK . Abdalla . J . Kunos . G . Iyer . MR . Cinar . R . Peripheral Hybrid CB(1)R and iNOS Antagonist MRI-1867 Displays Anti-Fibrotic Efficacy in Bleomycin-Induced Skin Fibrosis. . Frontiers in Endocrinology . 2021 . 12 . 744857 . 10.3389/fendo.2021.744857 . free . 34650521 . 8505776 .
  9. Roger . Célia . Buch . Chloé . Muller . Tania . Leemput . Julia . Demizieux . Laurent . Passilly-Degrace . Patricia . Cinar . Resat . Iyer . Malliga R. . Kunos . George . Vergès . Bruno . Degrace . Pascal . Jourdan . Tony . Simultaneous Inhibition of Peripheral CB1R and iNOS Mitigates Obesity-Related Dyslipidemia Through Distinct Mechanisms . Diabetes . 1 October 2020 . 69 . 10 . 2120–2132 . 10.2337/db20-0078. 32680936 . 7506827 .

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