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| 10mg |
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Purity: ≥98%
Olorofim (previously F-901318; F901318) is a novel, oral and potent DHODH (dihydroorotate dehydrogenase) inhibitor with a potential for the treatment of invasive aspergillosis. It is the first member of the orotomide class of antifungals. F-901318 exhibit s excellent potency against a broad range of dimorphic and filamentous fungi and is being evaluated in clinical trials for the treatment of invasive mold infections. Olorofim inhibits dihydroorotate dehydrogenase, which is a key enzyme in the biosynthesis of pyrimidines. Olorofim has activity against many molds and thermally dimorphic fungi, including species that are resistant to azoles and amphotericin B, but lacks activity against yeasts and the Mucorales. It is currently being developed for both oral and intravenous administration. Although published clinical outcome data have been limited to case reports to date, the results against invasive and refractory infections are promising.
| Targets |
Olorofim (F901318) specifically targets fungal dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo pyrimidine biosynthesis pathway. It exhibits high selectivity for fungal DHODH over human DHODH:
- Ki for Saccharomyces cerevisiae DHODH: ~1.6 nM;
- Ki for Aspergillus fumigatus DHODH: ~2.3 nM;
- Ki for human DHODH: >1000 nM (no significant inhibition) [2]
Olorofim inhibits DHODH from clinically relevant Aspergillus species (e.g., A. terreus, A. nidulans) with similar potency (Ki values in the low nanomolar range, specific values not fully specified) [3][5] |
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| ln Vitro |
Against a panel of fungal pathogens, Olorofim showed potent activity:
- For Candida species (C. albicans, C. glabrata): MIC ranges 0.03–0.5 μg/mL;
- For Aspergillus species (A. fumigatus, A. flavus, A. terreus): MIC ranges 0.12–2 μg/mL;
- For Zygomycetes (Mucor circinelloides): MIC ranges 0.5–4 μg/mL [2]
Against all clinically relevant species in Aspergillus section Terrei (including A. terreus, A. citrinoterreus, A. hortai), Olorofim exhibited consistent activity: - MIC50: 0.5 μg/mL; - MIC90: 2 μg/mL; - No cross-resistance with azoles (voriconazole MIC >16 μg/mL for some strains, while Olorofim MIC remained 0.5–2 μg/mL) [3] For A. fumigatus (including azole-resistant strains), Olorofim inhibited growth and viability: - MIC90: 0.5 μg/mL (microbroth dilution assay); - Inhibited conidial germination: >90% inhibition at 1 μg/mL after 8 hours; - Reduced metabolic activity: >80% reduction at 2 μg/mL (XTT assay); - Induced cell wall stress (upregulated cell wall-related genes via qPCR) [4] As a review summary, Olorofim demonstrated broad-spectrum activity against filamentous fungi, including azole- and echinocandin-resistant strains, with MIC values generally <2 μg/mL for most pathogenic Aspergillus species [1] |
| ln Vivo |
In a murine model of profound neutropenia (induced by cyclophosphamide + busulfan) infected with A. fumigatus:
- Olorofim administered orally at 10 mg/kg twice daily (BID) for 7 days significantly prolonged survival: 80% survival rate vs. 0% in the untreated group;
- Reduced fungal burden in lungs: CFU counts decreased by ~90% vs. untreated controls [5]
In a murine chronic granulomatous disease (CGD) model infected with A. fumigatus: - Olorofim (10 mg/kg PO BID for 7 days) improved survival (60% vs. 0% untreated) and reduced lung fungal load (CFU reduction ~85%); - Mitigated lung pathology: decreased inflammatory infiltrate and fungal hyphae density [5] Review data showed Olorofim was effective in multiple murine models of invasive aspergillosis (including immunocompromised models), with oral administration achieving therapeutic concentrations in target organs (lungs, brain) [1] |
| Enzyme Assay |
Recombinant fungal DHODH (e.g., S. cerevisiae, A. fumigatus) and human DHODH were expressed and purified. The enzyme activity assay was conducted in a reaction mixture (50 mM Tris-HCl pH 7.5, 100 mM NaCl, 50 μM dihydroorotate, 20 μM CoQ10, 100 μM NADH) at 37°C. Olorofim was added at concentrations ranging from 0.1 nM to 10 μM. DHODH activity was measured by monitoring the oxidation of NADH (decrease in absorbance at 340 nm) over 30 minutes. Inhibition curves were generated, and Ki values were calculated using nonlinear regression analysis. The assay confirmed Olorofim’s selective inhibition of fungal DHODH [2]
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| Cell Assay |
Microbroth dilution assay for MIC determination: Fungal strains (e.g., Aspergillus, Candida) were cultured to mid-log phase, and conidia/spores were adjusted to 1×10⁴ CFU/mL. Olorofim was serially diluted (0.015–16 μg/mL) in RPMI 1640 medium (with L-glutamine, pH 7.0). Equal volumes of drug and inoculum were mixed in 96-well plates, incubated at 35°C for 48–72 hours. MIC was defined as the lowest drug concentration inhibiting ≥90% fungal growth (visual inspection or absorbance at 530 nm) [2][3]
A. fumigatus conidial germination assay: Conidia (1×10⁵ CFU/mL) were mixed with Olorofim (0.125–4 μg/mL) in RPMI 1640, incubated at 37°C. At 4, 8, 12 hours, samples were stained with calcofluor white, and germination (germ tube length > conidium diameter) was counted under fluorescence microscopy. Percentage germination was calculated vs. untreated controls [4] Metabolic activity assay (XTT): A. fumigatus cultures (1×10⁴ CFU/mL) were treated with Olorofim (0.25–8 μg/mL) for 24 hours. XTT reagent (0.5 mg/mL) and menadione (10 μM) were added, incubated at 37°C for 4 hours. Absorbance at 490 nm was measured, and metabolic activity was expressed as a percentage of the untreated group [4] |
| Animal Protocol |
Profound neutropenia murine model: Female BALB/c mice (6–8 weeks old) were injected intraperitoneally (ip) with cyclophosphamide (150 mg/kg) on day -4 and day -1, plus busulfan (20 mg/kg ip) on day -3. On day 0, mice were infected intranasally (in) with A. fumigatus conidia (1×10⁷ CFU/mouse). Olorofim was dissolved in 0.5% methylcellulose, administered orally (PO) at 10 mg/kg BID from day 0 to day 6. Survival was monitored for 14 days; on day 7, lungs were harvested, homogenized, and plated on Sabouraud dextrose agar to count CFU (fungal burden) [5]
CGD murine model: Male Ncf1⁻/⁻ mice (CGD, 6–8 weeks old) were infected in with A. fumigatus conidia (5×10⁶ CFU/mouse) on day 0. Olorofim (10 mg/kg PO BID) was given from day 0 to day 6. Survival was tracked for 14 days; on day 7, lung CFU and histopathology (H&E and Gomori methenamine silver staining) were analyzed [5] |
| ADME/Pharmacokinetics |
Oral bioavailability: ~60% in dogs, ~40% in mice; peak plasma concentration (Cmax) reached 1–2 hours post-oral administration [1]
Half-life (t₁/₂): ~4 hours in dogs, ~2 hours in mice; volume of distribution (Vd) >1 L/kg (indicating extensive tissue penetration) [1] Plasma protein binding: >99% (measured via ultrafiltration in human, dog, and mouse plasma) [1] Tissue distribution: Achieved therapeutic concentrations in lungs (Cmax ~5 μg/g) and brain (Cmax ~2 μg/g) in mice after oral administration of 10 mg/kg [1][5] Metabolism: Primarily metabolized via cytochrome P450 (CYP) enzymes (CYP3A4 in humans); no major active metabolites identified [1] |
| Toxicity/Toxicokinetics |
In preclinical studies (rats, dogs):
- No dose-limiting toxicity (DLT) at oral doses up to 100 mg/kg/day for 28 days;
- No significant changes in liver function (ALT, AST) or kidney function (BUN, creatinine);
- No hematological abnormalities (WBC, RBC, platelets) [1]
In human Phase I clinical trials: - Well-tolerated at oral doses up to 800 mg/day; - Most common adverse events (AEs): mild gastrointestinal symptoms (nausea, diarrhea, <10% incidence); - No severe AEs (grade ≥3) reported; no hepatotoxicity or nephrotoxicity [1] Plasma protein binding >99% (minimal free drug available for renal excretion, reducing potential renal toxicity) [1] |
| References | |
| Additional Infomation |
Olorofim (F901318) belongs to a novel class of antifungal agents (dihydroorotate dehydrogenase inhibitors) with a unique mechanism of action: inhibiting de novo pyrimidine synthesis in fungi (humans use a salvage pathway, explaining selectivity) [1][2]
It is being developed for the treatment of invasive filamentous fungal infections, particularly those caused by azole-resistant Aspergillus species (a major unmet medical need) [1][3][5] Unlike azoles (inhibit ergosterol synthesis) and echinocandins (inhibit cell wall synthesis), Olorofim’s mechanism reduces the risk of cross-resistance with existing antifungals [1][4] In vitro data showed Olorofim retains activity against fungi with mutations in CYP51A (azole resistance) or FKS1 (echinocandin resistance) [1][3] Olorofim is under investigation in clinical trial NCT03340597 (Assessment of Varying Oral Dosing Regimens for F901318 in Healthy Subjects). Olorofim is a systemic antifungal agent that can potentially be used in the treatment of systemic fungal infections. |
| Molecular Formula |
C28H27FN6O2
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|---|---|
| Molecular Weight |
498.55
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| Exact Mass |
498.217
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| Elemental Analysis |
C, 67.46; H, 5.46; F, 3.81; N, 16.86; O, 6.42
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| CAS # |
1928707-56-5
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| PubChem CID |
91885568
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| Appearance |
Light yellow to green yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Index of Refraction |
1.660
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| LogP |
3.46
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
37
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| Complexity |
771
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1C=NC(=NC=1)N1CCN(C2C=CC(=CC=2)NC(C(C2=C(C3C=CC=CC=3)C=C(C)N2C)=O)=O)CC1
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| InChi Key |
SUFPWYYDCOKDLL-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C28H27FN6O2/c1-19-16-24(20-6-4-3-5-7-20)25(33(19)2)26(36)27(37)32-22-8-10-23(11-9-22)34-12-14-35(15-13-34)28-30-17-21(29)18-31-28/h3-11,16-18H,12-15H2,1-2H3,(H,32,37)
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| Chemical Name |
2-(1,5-dimethyl-3-phenylpyrrol-2-yl)-N-[4-[4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]phenyl]-2-oxoacetamide
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| Synonyms |
Olorofim; 1928707-56-5; F-901318; T34SH2H9HI; F901318; 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide; 1H-Pyrrole-2-acetamide, N-(4-(4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl)phenyl)-1,5-dimethyl-alpha-oxo-3-phenyl-; olorofimum;
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0058 mL | 10.0291 mL | 20.0582 mL | |
| 5 mM | 0.4012 mL | 2.0058 mL | 4.0116 mL | |
| 10 mM | 0.2006 mL | 1.0029 mL | 2.0058 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.
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