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Abacavir acetate (Prurisol; abacavir hydroxyacetate; KM-133) is a potent and orally bioactive inhibitor of IL-20 and PRINS used for the treatment of plaque psoriasis. It can reduce the proliferation rate of skin in psoriasis as an immune modulator, and thus can be used for treating inflammatory skin problems.
| Targets |
Abacavir is a carbocyclic synthetic nucleoside analogue. Following oral administration, it is taken up into cells and converted by cellular enzymes (primarily alcohol dehydrogenase and glucuronyl transferase) to the active metabolite carbovir triphosphate (CBV-TP), an analogue of the natural substrate deoxyguanosine-5′-triphosphate (dGTP). CBV-TP exerts its antiviral activity by competitively inhibiting HIV-1 reverse transcriptase (RT)—the key viral enzyme that converts viral RNA into DNA—and by chain termination after incorporation into the growing viral DNA strand. The inhibition constant (Ki) of CBV-TP for HIV-1 reverse transcriptase was reported at 0.021 µM using calf thymus DNA template-primer.
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| ln Vitro |
Abacavir exhibits potent in vitro antiviral activity against wild-type HIV-1. In MT-4 cells, the IC₅₀ was approximately 4.0 µM, which is lower than that of zidovudine (AZT, IC₅₀ 0.040 µM). However, against clinical HIV-1 isolates, abacavir showed a mean EC₅₀ of 0.26 ± 0.18 µM, comparable to that of AZT (0.23 µM). In primary cells including monocytes/macrophages and peripheral blood mononuclear cells (PBMCs), EC₅₀ values ranged from 3.7 to 5.8 µM against laboratory strain HIV-1IIIB and from 0.07 to 1.0 µM against clinical isolate HIV-1BaL. The median EC₅₀ values against HIV-1 clades A–G ranged from 8.1 nM to 356 nM. Against HIV-2 isolates (n = 4), EC₅₀ values ranged from 0.024 to 0.49 µM. Antiviral activity was not antagonized when combined with other NRTIs, NNRTIs, or protease inhibitors. The in vitro cytotoxicity (CC₅₀) values were 160 µM in CEM cells, 140 µM in CD4⁺ CEM cells, and 110 µM in normal bone progenitor cells (BFU-E).
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| ln Vivo |
In mice, oral abacavir glycolate (10–20 mg/kg) once daily efficiently reduces psoriasis [2].
In an animal model using conventional mice infected with chimeric HIV-1 (EcoHIV/NDK), abacavir administered orally at 100 mg/kg/day caused 96% inhibition of viral DNA synthesis in the spleen and almost completely abolished viral spliced RNA synthesis in both spleens and macrophages. In a separate efficacy model, groups of 5–7 mice were pretreated with the test drug prior to infection, with treatment continued for an additional 48 hours post-infection; viral DNA and RNA burdens in spleens and macrophages were then quantified by real-time PCR. These results demonstrated a statistically significant reduction in viral burdens compared to vehicle-treated controls (P < 0.001). |
| Enzyme Assay |
The inhibition of HIV-1 reverse transcriptase by the active metabolite of abacavir can be studied using in vitro gel‑based primer‑extension assays with radiolabeled nucleotides. In a typical protocol, purified recombinant HIV-1 reverse transcriptase is incubated with a synthetic DNA/RNA template‑primer, the four natural deoxyribonucleoside triphosphates (dNTPs, including radiolabeled dGTP), and varying concentrations of carbovir triphosphate (CBV‑TP). The reaction is initiated by the addition of the enzyme, allowed to proceed at 37°C for 15–30 minutes, and then terminated by heating. Reaction products are resolved by denaturing polyacrylamide gel electrophoresis and the extended primer bands are visualized and quantified by autoradiography or phosphorimaging. Competitive inhibition is assessed by measuring the incorporation efficiency of the nucleotide analogue compared to the natural substrate. The inhibition constant (Ki) has been determined to be 0.021 µM using a calf thymus DNA template primer.
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| Cell Assay |
The antiviral activity of abacavir against HIV-1 is typically assessed in primary human peripheral blood mononuclear cells (PBMCs) or established cell lines such as MT‑4 cells. In a standard susceptibility assay, PBMCs are isolated from healthy donors and activated with phytohemagglutinin (PHA). The cells are then infected with a reference HIV‑1 strain (e.g., HIV‑1IIIB or HIV‑1BaL) at a predetermined multiplicity of infection (MOI). Serial dilutions of abacavir (covering a concentration range typically from 0.001 µM to 100 µM) are added to the infected cells. Cultures are maintained for 5–7 days at 37°C in a humidified 5% CO₂ incubator. Antiviral activity is quantified by measuring HIV-1 p24 antigen production in the culture supernatant via ELISA, or by assessing viral RNA replication via real‑time RT‑PCR. The 50% effective concentration (EC₅₀) is calculated using non‑linear regression analysis. Cytotoxicity is evaluated in parallel in uninfected cells using a colorimetric assay (such as MTT or XTT) to determine the CC₅₀ (50% cytotoxic concentration). The therapeutic index is then calculated as the ratio CC₅₀/EC₅₀.
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| Animal Protocol |
Animal/Disease Models: 6 to 8 weeks old male and female SCID (severe combined immunodeficient) mouse, implanted with psoriatic tissue [2]
Doses: 10 and 20 mg/kg Route of Administration: po (oral gavage); 10-20 mg/kg Primary Experimental Results:Reduction The concentration of PRINS and 1L-20 reduces the area of skin lesions. Shows better results than methotrexate in controlling psoriasis. In an antiretroviral efficacy model, conventional immunocompetent mice (5–7 per group) are pretreated with abacavir (typically 100 mg/kg/day by oral gavage) or vehicle control for a specified period. The mice are then infected intraperitoneally with a chimeric HIV-1 (EcoHIV/NDK) constructed on the backbone of subtype D NDK. Treatment is maintained for an additional 48 hours following infection. Animals are then euthanized, and spleens and peritoneal macrophages are collected. Viral DNA and RNA burdens are quantified by real‑time PCR (QPCR) and RT‑PCR, respectively. Viral protein burden can also be assessed by p24 ELISA. This model has demonstrated that abacavir at 100 mg/kg/day causes 96% inhibition of viral DNA synthesis in the spleen and almost completely eliminates spliced viral RNA synthesis. |
| ADME/Pharmacokinetics |
Following oral administration, abacavir is rapidly absorbed, with an absolute oral bioavailability of approximately 83% (geometric mean). The time to peak plasma concentration (tmax) is about 1.5 hours for tablets and 1 hour for oral solution. After oral administration of 300 mg twice daily, steady‑state peak concentration (Cmax) is approximately 3.0 ± 0.89 mcg/mL and AUC(0‑12h) is 6.02 ± 1.73 mcg·h/mL. After a single 600 mg dose, Cmax is 4.26 ± 1.19 mcg/mL and AUC∞ is 11.95 ± 2.51 mcg·h/mL. The observed elimination half‑life (t½) is 1.54 ± 0.63 hours. The apparent volume of distribution is 0.86 ± 0.15 L/kg, with approximately 50% plasma protein binding. Cerebrospinal fluid AUC(0‑6h) to plasma AUC(0‑6h) ratio ranges from 27% to 33%. Abacavir is not significantly metabolized by cytochrome P450 enzymes; it is primarily metabolized by alcohol dehydrogenase to the 5′‑carboxylic acid and by glucuronyl transferase to the 5′‑glucuronide. The metabolites are inactive. About 1.2% of the dose is excreted unchanged in urine; 30% is excreted as the 5′‑carboxylic acid metabolite, 36% as the 5′‑glucuronide metabolite, and 15% as unidentified minor metabolites. Fecal excretion accounts for 16% of the dose. The pharmacokinetic properties are dose‑independent over a range of 300–1200 mg per day. Food does not affect bioavailability significantly.
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| Toxicity/Toxicokinetics |
Abacavir carries a Boxed Warning for serious and sometimes fatal hypersensitivity reactions, which occur as a multi‑organ clinical syndrome typically including fever and/or rash. Hypersensitivity is strongly associated with the HLA‑B57:01 allele; screening for this allele is required prior to treatment initiation. Patients who test positive for HLA‑B57:01 should not receive abacavir. Rechallenge after a suspected hypersensitivity reaction is contraindicated due to risk of rapid recurrence and death. In addition, lactic acidosis and severe hepatomegaly with steatosis have been reported. Hematologic toxicities, particularly neutropenia, have been observed. In 2‑year carcinogenicity studies, oral administration of abacavir in mice and rats resulted in malignant tumors in the preputial (males) and clitoral (females) glands and in the liver of female rats, at systemic exposures approximately 6–32 times the human exposure at 600 mg. Abacavir induced chromosomal aberrations in cultured human lymphocytes (with and without metabolic activation) and was clastogenic in a mouse bone marrow micronucleus assay in males. Myocardial degeneration was also observed in mice and rats after 2 years of administration, at exposures 7–24 times the human exposure at 600 mg. In clinical trials, the 600 mg once‑daily regimen was associated with a higher incidence of severe hypersensitivity reactions and severe diarrhea compared to the 300 mg twice‑daily regimen. Abacavir does not impair fertility in rats at exposures up to approximately 3‑ to 4‑fold the human AUC.
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| References |
[1]. Guda A, et al. Investigational drugs in phase II clinical trials for moderate to severe plaque psoriasis - potential new treatments on the horizon. Expert Opin Investig Drugs. 2018 Nov;27(11):931-939.
[2]. Menon, et al. CARBOCYCLIC NUCLEOSIDES AND THEIR PHARMACEUTICAL USE AND COMPOSITIONS. WO/2013/103601/Al. |
| Additional Infomation |
Prurisol is currently being investigated for the treatment of chronic stable plaque psoriasis. Prurisol has previously been investigated for the treatment of plaque psoriasis.
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| Molecular Formula |
C16H20N6O3
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|---|---|
| Molecular Weight |
344.37
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| Exact Mass |
344.16
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| Elemental Analysis |
C, 55.80; H, 5.85; N, 24.40; O, 13.94
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| CAS # |
1446418-48-9
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| Related CAS # |
136470-78-5;136777-48-5 (HCl);168146-84-7 (succinate);188062-50-2 (sulfate); 1446418-48-9 (hydroxyacetate); 384380-52-3 (caeboxylate);
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| PubChem CID |
71605071
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| Appearance |
Solid powder
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| LogP |
0.638
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
25
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| Complexity |
528
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| Defined Atom Stereocenter Count |
2
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| SMILES |
O(C(CO)=O)C[C@@H]1C=C[C@@H](C1)N1C=NC2C1=NC(N)=NC=2NC1CC1
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| InChi Key |
ZBBZROWQLKCFQK-KOLCDFICSA-N
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| InChi Code |
InChI=1S/C16H20N6O3/c17-16-20-14(19-10-2-3-10)13-15(21-16)22(8-18-13)11-4-1-9(5-11)7-25-12(24)6-23/h1,4,8-11,23H,2-3,5-7H2,(H3,17,19,20,21)/t9-,11+/m1/s1
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| Chemical Name |
((1S,4R)-4-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)cyclopent-2-en-1-yl)methyl 2-hydroxyacetate
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| Synonyms |
PrurisolKM133 KM 133KM-133 Abacavir hydroxyacetateAbacavir acetate
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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 (~290.39 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.26 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (7.26 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 25.0 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 | 2.9039 mL | 14.5193 mL | 29.0385 mL | |
| 5 mM | 0.5808 mL | 2.9039 mL | 5.8077 mL | |
| 10 mM | 0.2904 mL | 1.4519 mL | 2.9039 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 |
| NCT02101216 | COMPLETED | Drug: Prurisol Drug: Ziagen |
Psoriasis | Cellceutix Corporation | 2014-03 | Phase 1 |
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