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| Targets |
ABX464 targets the HIV-1 Rev protein and capsid-binding complex (CBC), inhibiting viral RNA splicing and export. It also upregulates anti-inflammatory miR-124 by splicing long non-coding RNA 205 (lncRNA 205).
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| ln Vitro |
HIV-1 generation in PBMC and macrophage-infected cells is inhibited by obefazimod. When tested against all identified HIV-1 subtypes, including subtypes B, C, and recombinant viruses, obefazimod demonstrates a potent inhibitory effect. Additionally, ofazimod is particularly successful at preventing viral strains with mutations that give them resistance to various treatment drugs from replicating in vitro. While Obefazimod suppressed the K65R and M184V mutant strains, the antiviral medication 3TC was not very effective against them. In order to replicate the impact of Obefazimod on HIV-1 replication in additional primary cells, p24 antigen levels in the culture supernatants were tracked for a duration of 12 days after cells were treated with Obefazimod at concentrations ranging from 0.01 μM to 30 μM. Obefazimod, whose IC50 ranges from 0.1 μM to 1 μM, efficiently inhibits viral replication in a dose-dependent manner [1].
In HIV-infected primary CD4+ T cells, ABX464 (0.1–1 μM) reduced viral RNA levels by >90% and blocked viral replication without cytotoxicity. Mechanistically, it binds CBC to prevent Rev-mediated export of unspliced HIV-1 transcripts. In SARS-CoV-2-infected human respiratory epithelial models, ABX464 (10 μM) inhibited viral replication by >80% via RT-qPCR, likely through miR-124-mediated suppression of dynamin 2 (a viral entry protein). |
| ln Vivo |
The in vivo effectiveness of obazimod may be tested quickly, consistently, and reproducibly using humanized mice reconstituted with human lymphocytes. PBMC was used to reestablish SCID mice in an initial setup, and the HIV-1 strain JR-CSF was then introduced. For 15 days, mice were given 20 mg/kg of obefazimod orally twice a day (bid). Viral RNA measurements revealed that during the course of the 15-day treatment, oral obazimod medication considerably decreased the viral load. Blood samples were subjected to FACS analysis, which revealed that Obefazimod therapy prevented the recombinant mice's CD8+/CD4+ ratio from falling below that of uninfected mice following infection [1].
In humanized mice with chronic HIV infection, ABX464 (50 mg/kg/day orally for 4 weeks) reduced plasma viral load by >2 log10 and delayed viral rebound after treatment cessation. In ulcerative colitis (UC) Phase 3 trials (ABTECT-1/2), ABX464 (25/50 mg/day) induced clinical remission in 11.3–23.8% of patients (vs. 2.5–6.3% placebo) at Week 8, with endoscopic improvement in 22.0–37.5% (vs. 5.7–10.1% placebo). |
| Cell Assay |
For HIV studies: Primary CD4+ T cells were infected with HIV-1 and treated with ABX464 (0.1–10 μM). Viral RNA was quantified by RT-PCR, and cytotoxicity was assessed via ATP-based assays. The drug selectively spliced viral RNA without affecting host RNA.
For UC studies: Colonic biopsies from patients showed increased miR-124 levels after ABX464 treatment, correlating with reduced TNF-α, IL-6, and other pro-inflammatory cytokines. |
| ADME/Pharmacokinetics |
HIV Studies: Primary CD4+ T cells were infected with HIV-1 and treated with ABX464 (0.1–10 μM). Viral RNA was quantified by RT-PCR, and cytotoxicity was assessed using an ATP-based assay. This drug selectively splices viral RNA without affecting host RNA. UC Studies: Colon biopsies of patients showed elevated miR-124 levels after ABX464 treatment, which were associated with decreased levels of TNF-α, IL-6, and other pro-inflammatory cytokines.
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| Toxicity/Toxicokinetics |
In the UC trial, hyperkalemia (dose-related) occurred in 1.6%–11.3% of patients. No serious adverse events or cortisol deficiency were reported.
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| References | |
| Additional Infomation |
ABX-464 is currently undergoing clinical trial NCT03905109 (Safety evaluation of ABX464 in patients with moderate to severe active Crohn's disease). Oberazimod is an orally administered small molecule drug that binds to the cap-binding complex (CBC) 80/20 and possesses potential antiviral and anti-inflammatory activity. After oral administration, oberazimod binds to CBC, a complex located at the 5' end of the precursor mRNA transcript that promotes its initial interaction with transcriptional and processing mechanisms. This leads to a conformational change in CBC, enhancing splicing of viral RNA variants and upregulating the anti-inflammatory microRNA miR-124 by splicing long non-coding RNA at the miR-124-1 site. In human immunodeficiency virus type 1 (HIV-1) infected cells, oberazimod interacts with the CBC domain of HIV-1 mRNA and inhibits viral replication by preventing Rev-mediated export of unspliced HIV-1 transcripts to the cytoplasm. Rev promotes the nuclear export of unspliced or incompletely spliced viral precursor mRNA, a key step in HIV-1 replication. Under inflammatory conditions, miR-124 reduces the production of various inflammatory mediators, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and CC motif chemokine 2 (CCL2; MCP-1). miR-124 plays a crucial role in both innate and adaptive immune responses and is an important mediator of cholinergic anti-inflammatory effects. Drug Indications For the treatment of Crohn's disease and ulcerative colitis. Additional Information: ABX464 is a first-in-class oral medication that exerts dual anti-HIV and anti-inflammatory effects by upregulating miR-124. Its efficacy in treating ulcerative colitis, Crohn's disease, and COVID-19 is currently under investigation.
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| Molecular Formula |
C16H10CLF3N2O
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| Molecular Weight |
338.71
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| Exact Mass |
338.043
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| Elemental Analysis |
C, 56.74; H, 2.98; Cl, 10.47; F, 16.83; N, 8.27; O, 4.72
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| CAS # |
1258453-75-6
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| PubChem CID |
49846599
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
412.3±45.0 °C at 760 mmHg
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| Flash Point |
203.2±28.7 °C
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| Vapour Pressure |
0.0±1.0 mmHg at 25°C
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| Index of Refraction |
1.629
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| LogP |
4.21
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
23
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| Complexity |
388
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1=CC=CC2=CC=C(N=C21)NC1C=CC(=CC=1)OC(F)(F)F
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| InChi Key |
OZOGDCZJYVSUBR-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H10ClF3N2O/c17-13-3-1-2-10-4-9-14(22-15(10)13)21-11-5-7-12(8-6-11)23-16(18,19)20/h1-9H,(H,21,22)
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| Chemical Name |
8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine
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| Synonyms |
Obefazimod; Obefazimodum; Obéfazimod; ABX-464; ABX464; 1258453-75-6; obefazimod; 8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine; 8-Chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine; 26RU378B9V; SPL464; ABX 464; SPL 464; SPL-464
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ≥ 100 mg/mL (~295.24 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3.75 mg/mL (11.07 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 37.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 3.75 mg/mL (11.07 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 37.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.9524 mL | 14.7619 mL | 29.5238 mL | |
| 5 mM | 0.5905 mL | 2.9524 mL | 5.9048 mL | |
| 10 mM | 0.2952 mL | 1.4762 mL | 2.9524 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05177835 | Active, not recruiting | Drug: ABX464 | Ulcerative Colitis | Abivax S.A. | December 3, 2021 | Phase 2 |
| NCT04049448 | Completed | Drug: ABX464 | Rheumatoid Arthritis | Abivax S.A. | October 24, 2019 | Phase 2 |
| NCT05121714 | Completed | Drug: Caffeine Drug: ABX464 |
Healthy | Abivax S.A. | December 17, 2020 | Phase 1 |
| NCT03093259 | Completed Has Results | Drug: ABX464 Drug: Placebo oral capsule |
Ulcerative Colitis | Abivax S.A. | November 16, 2017 | Phase 2 |
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