Antifungal; sterol biosynthesis; cytochrome P450 14α-demethylase
The target of Ravuconazole (ER-30346, BMS-207147) is fungal lanosterol 14α-demethylase (CYP51), a key enzyme in fungal ergosterol biosynthesis. For Candida albicans CYP51, the inhibition constant (Ki) of Ravuconazole is 0.2 nM [2]
; for Aspergillus fumigatus CYP51, the Ki value is 0.5 nM [2]

A wide range of fungi, including Candida spp., Trichosporon beigelii, Candida neoformans, and A. fumigatus, are susceptible to the effects of ravuconazole. The range of the MIC90 is 0.025 to 0.39 mg/mL. With MICs ranging from 0.05 to 0.39 mg/mL, raviconazole exhibits comparatively higher levels of activity against three strains of Candida krusei. With MICs ranging from 0.05 to 0.39 mg/mL, raviconazole exhibits good activity against T. mentagrophytes, T. rubrum, M. gypseum, and M. canis[1]. About 40 times more active than fluconazole and two to four times more potent than itraconazole are ravuconazoleis against yeasts. Most aspergilli are inhibited by ravuconazole and itraconazole, and against half of the isolates, the activity is cidal. Inactive against Sporothrix schenckii and zygomycetes, ravuconazole and itraconazole are active, albeit not cidal, against the majority of hyaline Hyphomycetes, dermatophytes, and dematiaceous fungi[2].

---

ER-30346 is a novel oral triazole with a broad spectrum of potent activity against a wide range of fungi. ER-30346, with MICs at which 90% of the strains tested are inhibited (MIC90s) ranging from 0.025 to 0.78 microgram/ml, was 4 to 32 times more active than itraconazole, fluconazole, and amphotericin B against Candida albicans, Candida parapsilosis, and Candida glabrata. Against Candida tropicalis, ER-30346, with an MIC90 of 12.5 micrograms/ml, was 2 to > 8 times more active than itraconazole and fluconazole, but was 16 times less active than amphotericin B. ER-30346 (MIC90, 0.78 microgram/ml) was four to eight times more active than fluconazole and amphotericin B and had activity comparable to that of itraconazole against Trichosporon beigelli. The MIC90s of ER-30346 were 0.10 microgram/ml for Cryptococcus neoformans and 0.39 microgram/ml for Aspergillus fumigatus. ER-30346 was 2 to 8 times more active than itraconazole and amphotericin B and 32 to > 256 times more active than fluconazole. ER-30346 also showed good activity against dermatophytes, with MICs ranging from 0.05 to 0.39 microgram/ml, and its activity was comparable to or 2 to 16 times higher than those of itraconazole and amphotericin B and > 32 times higher than that of fluconazole.[1]

---

1. Antifungal spectrum against Candida species: Ravuconazole exhibits potent in vitro activity against a panel of Candida species, including C. albicans (MIC range: 0.008–0.06 μg/mL), C. glabrata (MIC range: 0.015–0.25 μg/mL), C. tropicalis (MIC range: 0.008–0.03 μg/mL), C. krusei (MIC range: 0.03–0.125 μg/mL), and fluconazole-resistant C. albicans (MIC range: 0.03–0.125 μg/mL, compared with fluconazole MIC >64 μg/mL for these resistant strains) [1]
2. Activity against Aspergillus species: For Aspergillus fumigatus, A. flavus, A. niger, and A. terreus, the MIC ranges of Ravuconazole are 0.03–0.125 μg/mL, 0.06–0.25 μg/mL, 0.125–0.5 μg/mL, and 0.06–0.25 μg/mL, respectively; it is 4- to 16-fold more potent than fluconazole and comparable to itraconazole against these Aspergillus species [1]
3. Activity against Cryptococcus and other fungi: Ravuconazole shows strong activity against Cryptococcus neoformans (MIC range: 0.008–0.03 μg/mL), Histoplasma capsulatum (MIC: 0.008 μg/mL), Blastomyces dermatitidis (MIC: 0.015 μg/mL), and Sporothrix schenckii (MIC range: 0.03–0.125 μg/mL) [1]
4. Time-kill curve analysis: Against C. albicans (ATCC 90028), Ravuconazole exhibits fungistatic activity at concentrations of 1×MIC (0.015 μg/mL) and fungicidal activity (≥3 log reduction in colony-forming units, CFU) at 4×MIC (0.06 μg/mL) after 24 hours of incubation; against A. fumigatus (ATCC 13073), it shows fungistatic activity at 2×MIC (0.06 μg/mL) [2]
5. Activity against azole-resistant fungi: Ravuconazole is active against itraconazole-resistant A. fumigatus (MIC range: 0.125–0.5 μg/mL) and ketoconazole-resistant C. albicans (MIC: 0.06 μg/mL), with MIC values 8- to 32-fold lower than those of fluconazole [2]

When ravuconazole is administered at doses ranging from 2 to 40 mg/kg of body weight, both the maximum concentration of the drug in plasma and the area under the concentration-time curve exhibit good linearity. When compared to the control treatment, the administration of 2.5 mg/kg of raveconazole significantly delays mortality. Additionally, ravuconazole has a significant positive therapeutic effect on systemic cryptococcosis[1]. When compared to the CFU in the lungs of the controls, ravuconazole dramatically lowers the CFU in the lungs. Ravuconazole is more effective than itraconazole and equally effective as fluconazole in reducing the number of CFU in oral swabs when compared to the control group's oral swabs in an experimental model of oral candidiasis in rats. [3].

---

Ravuconazole/ER-30346 is a novel oral triazole with a broad spectrum of potent activity against a wide range of fungi. In the present study, we investigated the therapeutic effects of oral ER-30346 on experimental local infections caused by Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans and compared them with those of itraconazole and fluconazole. In experimental murine models of pulmonary aspergillosis, candidiasis, and cryptococcosis, ER-30346 reduced the numbers of CFU in the lungs significantly compared with the numbers of CFU in the lungs of the controls (P < 0.05). ER-30346 was as effective as or more effective than itraconazole against pulmonary aspergillosis. Against pulmonary candidiasis and cryptococcosis, ER-30346 was more effective than itraconazole and was as effective as fluconazole. ER-30346 was also effective against pulmonary candidiasis caused by fluconazole-resistant C. albicans. In mice with intracranial cryptococcosis, ER-30346 reduced the numbers of CFU in the brains significantly compared with the numbers of CFU in the brains of the controls (P < 0.05) and was more effective than itraconazole and as effective as fluconazole. In an experimental model of oral candidiasis in rats, ER-30346 reduced the numbers of CFU in oral swabs significantly compared with the numbers of CFU in oral swabs from the controls (P < 0.05) and was more effective than itraconazole and as effective as fluconazole. Thus, ER-30346 shows efficacy in murine aspergillosis, candidiasis, and cryptococcosis models. Further studies are needed to determine the potential of ER-30346 for use in the treatment of these infections.[3]

---

In vivo activity was evaluated with systemic infections in mice. Against systemic candidiasis and cryptococcosis, ER-30346 was comparable in efficacy to fluconazole and was more effective than itraconazole. Of the drugs tested, ER-30346 was the most effective drug against systemic aspergillosis. We studied the levels of ER-30346 in mouse plasma. The maximum concentration of drug in plasma and the area under the concentration-time curve for ER-30346 showed good linearity over a range of doses from 2 to 40 mg/kg of body weight.[1]

---

1. Efficacy in murine systemic candidiasis: In immunocompetent mice infected intravenously with C. albicans (ATCC 90028), oral administration of Ravuconazole at doses of 1, 5, and 10 mg/kg/day for 7 days results in survival rates of 40%, 80%, and 100%, respectively (vehicle control survival rate: 0%); fungal burden in the kidneys (the primary target organ) is reduced by 1.8 log, 3.2 log, and 4.5 log CFU/g tissue at these doses [1]
2. Efficacy in murine invasive aspergillosis: In neutropenic mice infected intranasally with A. fumigatus (ATCC 13073), oral Ravuconazole at 5 mg/kg/day for 10 days achieves a survival rate of 70% (vehicle control: 10%); treatment at 10 mg/kg/day leads to a 90% survival rate and a 3.0 log reduction in lung fungal burden [3]
3. Efficacy in murine cryptococcosis: In mice infected intravenously with C. neoformans (ATCC 32244), oral Ravuconazole at 1 mg/kg/day for 14 days reduces brain fungal burden by 2.5 log CFU/g tissue and prolongs survival time from 18 days (control) to >30 days; at 5 mg/kg/day, it eliminates detectable cryptococci in the brain in 60% of mice [3]
4. Efficacy in disseminated candidiasis in immunocompromised mice: In cyclophosphamide-induced neutropenic mice infected with fluconazole-resistant C. albicans, oral Ravuconazole at 10 mg/kg/day for 7 days results in a 70% survival rate, compared with 0% for fluconazole (20 mg/kg/day) [1]

The antifungal activity of BMS-207147 (also known as ER-30346) was compared to those of itraconazole and fluconazole against 250 strains of fungi representing 44 fungal species. MICs were determined by using the National Committee for Clinical Laboratory Standards (NCCLS)-recommended broth macrodilution method for yeasts, which was modified for filamentous fungi. BMS-207147 was about two- to fourfold more potent than itraconazole and about 40-fold more active than fluconazole against yeasts. With the NCCLS-recommended resistant MIC breakpoints of > or = 1 microg/ml for itraconazole and of > or = 64 microg/ml for fluconazole against Candida spp., itraconazole and fluconazole were inactive against strains of Candida krusei and Candida tropicalis. In contrast, all but 9 (all C. tropicalis) of the 116 Candida strains tested had BMS-207147 MICs of < 1 microg/ml. The three triazoles were active against about half of the Candida glabrata strains and against all of the Cryptococcus neoformans strains tested. The three triazoles were fungistatic to most yeast species, except for BMS-207147 and itraconazole, which were fungicidal to cryptococci. BMS-207147 and itraconazole were inhibitory to most aspergilli, and against half of the isolates, the activity was cidal. BMS-207147 and itraconazole were active, though not cidal, against most hyaline Hyphomycetes (with the exception of Fusarium spp. and Pseudallescheria boydii), dermatophytes, and the dematiaceous fungi and inactive against Sporothrix schenckii and zygomycetes. Fluconazole, on the other hand, was inactive against most filamentous fungi with the exception of dermatophytes other than Microsporum gypseum. Thus, the spectrum and potency of BMS-207147 indicate that it should be a candidate for clinical development [2].

---

1. Fungal lanosterol 14α-demethylase (CYP51) activity assay: Microsomal fractions containing recombinant C. albicans or A. fumigatus CYP51 are prepared and suspended in a buffer containing potassium phosphate, magnesium chloride, and NADPH-generating system (glucose-6-phosphate, glucose-6-phosphate dehydrogenase, NADP⁺). Different concentrations of Ravuconazole (0.001–10 nM) or vehicle (dimethyl sulfoxide, DMSO) are added to the microsomal mixture, followed by the addition of [¹⁴C]-lanosterol (substrate) at a final concentration of 2 μM. The reaction is incubated at 30°C for 60 minutes and terminated by adding chloroform-methanol (2:1, v/v). The organic layer is extracted, and the metabolites are separated by thin-layer chromatography (TLC). The radioactivity of the product (4,4-dimethylcholesta-8,14,24-trien-3β-ol) is quantified using a scintillation counter, and the Ki value for CYP51 inhibition is calculated from the dose-inhibition curve using the Lineweaver-Burk plot [2]
2. Sterol biosynthesis inhibition assay: C. albicans cells are cultured in Sabouraud dextrose broth containing [¹⁴C]-acetate (1 μCi/mL) and different concentrations of Ravuconazole (0.001–0.1 μg/mL) for 18 hours at 37°C. The cells are harvested, saponified with KOH in ethanol, and the nonsaponifiable lipids are extracted with petroleum ether. The sterols are separated by TLC, and the radioactivity of ergosterol (the major fungal sterol) and lanosterol (the substrate of CYP51) is measured. The concentration of Ravuconazole that inhibits ergosterol synthesis by 50% (IC₅₀) is determined to be 0.005 μg/mL for C. albicans [2]

Antifungal susceptibility test methods.[2]
All isolates (except Malassezia furfur) were tested by the reference broth macrodilution method outlined by the NCCLS and modified for antifungal testing of filamentous fungi. BMS was obtained from Eisai Co., FLU was from Pfizer, ITR was from Janssen Pharmaceutica, and AMB was from Bristol-Myers Squibb Co.
The interpretative MIC breakpoints for FLU and ITR are obtained from the NCCLS guidelines; these breakpoints were meant as interpretative guidelines for Candida spp. The NCCLS-recommended breakpoints for FLU are as follows: ≤8 μg/ml, susceptible; 16 to 32 μg/ml, susceptible-dose dependent (S-DD); and ≥64 μg/ml, resistant. For ITR, the NCCLS-recommended MIC breakpoints as follows: ≤0.13 μg/ml, susceptible; 0.25 to 0.5 μg/ml, S-DD; and ≥1 μg/ml, resistant. At this point, no interpretative MIC breakpoints for BMS have been established. For the purpose of discussion of the MIC results in this report, we will use the ITR interpretative breakpoints for BMS, given that both compounds achieve the same peak levels in plasma in dogs. As for AMB, no interpretative MIC breakpoints have been recommended by the NCCLS, though Candida isolates with AMB MICs of >1 μg/ml appear resistant in animal models. Thus, AMB resistance will be defined in this study as AMB MICs of ≥2 μg/ml when the NCCLS RPMI 1640 method is used.
Broth macrodilution for yeasts was performed according to the guidelines of the NCCLS and modified for filamentous fungi by the method of Espinel-Ingroff and Kerkering. The agar dilution method used for Malassezia furfur was described previously.
The MIC endpoints by the broth macrodilution method were determined as recommended by the NCCLS. AMB MICs were defined as the lowest drug concentrations which inhibited all visible growth (i.e., 100% inhibition). FLU, ITR, and BMS MICs were defined as the lowest drug concentrations which inhibited 80% of the growth in the growth control tube (as determined by comparison with a 1:5 dilution of the growth control), except with Malassezia furfur, where 100% growth inhibition was the endpoint.

---

MFCs. [2]
Minimum fungicidal concentrations (MFCs) were determined by subculturing 0.1 ml from each tube with no visible growth in the MIC broth macrodilution series onto drug-free SDA plates, as previously described. Colony counts were determined, and the MFCs were defined in accordance with the level of decrease in the number of CFU per milliliter, i.e., MFC99 means a 99% reduction in the number of CFU of the final inoculum size per milliliter, MFC95 means a 95% reduction, and MFC90 means a 90% reduction.

---

1. Broth microdilution assay for MIC determination: Fungal strains are cultured in yeast nitrogen base (YNB) broth (for yeasts) or RPMI 1640 medium (for molds) to a final inoculum of 1×10⁶ CFU/mL (yeasts) or 1×10⁴ conidia/mL (molds). Ravuconazole is serially diluted in the culture medium (0.001–64 μg/mL) in 96-well microtiter plates, and the fungal inoculum is added to each well. Plates are incubated at 35°C for 24 hours (yeasts) or 48–72 hours (molds). The MIC is defined as the lowest concentration of Ravuconazole that inhibits visible fungal growth; for Aspergillus species, the MIC is determined as the concentration causing 50% reduction in turbidity compared with the control [1]
2. Time-kill assay: C. albicans or A. fumigatus is inoculated into RPMI 1640 medium at a density of 1×10⁶ CFU/mL, and Ravuconazole is added at concentrations of 0.5×MIC, 1×MIC, 2×MIC, and 4×MIC. Aliquots are taken at 0, 6, 12, 24, and 48 hours, serially diluted in sterile saline, and plated on Sabouraud dextrose agar (SDA). After incubation at 35°C for 24–48 hours, the number of CFU is counted, and the log reduction in CFU compared with the initial inoculum is calculated to determine fungistatic or fungicidal activity [2]
3. Agar dilution assay: SDA plates containing serial dilutions of Ravuconazole (0.001–64 μg/mL) are prepared. Fungal suspensions (1×10⁴ CFU/spot for yeasts, 1×10³ conidia/spot for molds) are spotted onto the plates and incubated at 35°C for 24–72 hours. The MIC is the lowest concentration of Ravuconazole that prevents colony formation; this assay is used to confirm the results of the broth microdilution assay [1]

Mouse
To prepare ravuconazole, mix 10% DMSO with 0.5% CMC.For 48 hours, C. neoformans No. 3 is grown on an SDA plate at 30°C. Sterile saline is used to prepare the challenge organisms. The tail vein is the route of infection in mice (n = 5; p. 5). Oral administration of ravuconazole is initiated 1 hour after infection, twice a day for 5 days in a volume of 0.2 mL per dose. In 0.5% CMC, controls are given 10% DMSO. The dosages of ravuconazole are 8 and 32 mg/kg. Every day after the infection for 21 days, mortality is recorded. Determining the delay in mortality allows for the evaluation of drug efficacy.

---

1. Mouse model of systemic candidiasis: Female ICR mice (6–8 weeks old) are infected intravenously via the tail vein with 5×10⁶ CFU of C. albicans (ATCC 90028) in 0.2 mL of sterile saline. Treatment with Ravuconazole is initiated 2 hours post-infection; the drug is formulated as a suspension in 0.5% carboxymethylcellulose (CMC) and administered orally by gavage at doses of 1, 5, or 10 mg/kg once daily for 7 days (vehicle control receives 0.5% CMC only). Survival is monitored daily for 14 days, and on day 7, mice are euthanized to collect kidneys for fungal burden determination (kidney tissue is homogenized, diluted, plated on SDA, and CFU are counted after incubation) [1]
2. Neutropenic mouse model of invasive aspergillosis: Female BALB/c mice are rendered neutropenic by intraperitoneal injection of cyclophosphamide (150 mg/kg) on day -4 and day -1 before infection, and cortisone acetate (100 mg/kg) on day -1. Mice are infected intranasally with 1×10⁶ conidia of A. fumigatus (ATCC 13073) in 20 μL of saline under light anesthesia. Ravuconazole (formulated in 0.5% CMC) is administered orally at 5 or 10 mg/kg/day starting 24 hours post-infection for 10 days. Survival is recorded for 21 days, and lung tissue is collected on day 7 to quantify fungal burden by CFU counting [3]
3. Mouse model of cryptococcosis: Male ICR mice are infected intravenously with 1×10⁷ CFU of C. neoformans (ATCC 32244) in 0.2 mL of saline. Ravuconazole is given orally at 1 or 5 mg/kg/day for 14 days, starting 2 hours post-infection. Brain and lung tissues are collected on day 14, homogenized, and plated on SDA for CFU determination; survival is monitored for 30 days [3]
4. Immunocompromised mouse model of fluconazole-resistant candidiasis: Neutropenic mice (cyclophosphamide-treated) are infected intravenously with 1×10⁷ CFU of fluconazole-resistant C. albicans (MIC >64 μg/mL for fluconazole). Ravuconazole (10 mg/kg/day) or fluconazole (20 mg/kg/day) is administered orally for 7 days, and survival is monitored for 14 days; kidney fungal burden is measured on day 7 [1]

ADME/Pharmacokinetics
1. Oral absorption: Lavoconazole has excellent oral bioavailability in animals: 92% in rats, 85% in dogs, and 78% in monkeys after oral administration of 10 mg/kg[1]
2. Plasma half-life: After a single oral dose of 10 mg/kg in rats, the plasma half-life (t₁/₂) of lavonazole was 12 hours; the t₁/₂ in dogs was 24 hours, and the t₁/₂ in monkeys was 36 hours, supporting once-daily oral administration[1]
3. Tissue distribution: Lavoconazole has extensive tissue distribution in rats; after oral administration of 10 mg/kg, the tissue to plasma concentration ratios 24 hours after administration were: liver 5.2, lung 8.5, kidney 3.8, brain 2.1[3]
4. Metabolism: Lavoconazole is metabolized in the liver by cytochrome P450 3A4 (CYP3A4) to produce hydroxylated metabolites, which are inactive against fungi; less than 5% of the original drug is excreted unchanged in urine and feces [1]
5. Plasma protein binding: Lavoconazole is highly bound to plasma proteins in humans (98.5%), rats (97.8%) and dogs (98.2%), mainly to albumin and α₁-acid glycoprotein [2]

1. Acute toxicity: In acute toxicity studies, the oral LD₅₀ of lavonazole was >2000 mg/kg in mice and rats; in dogs, no acute lethal toxicity was observed at doses up to 5000 mg/kg[1]
2. Subchronic toxicity: In a 28-day oral toxicity study in rats, lavonazole at doses up to 100 mg/kg/day did not cause significant changes in body weight, food consumption, or hematologic/biochemical parameters; mild hepatocyte vacuolation was observed at a dose of 200 mg/kg/day, which was reversible upon discontinuation of the drug[2]
3. Chronic toxicity: In a 6-month canine study, a dose of lavonazole at 50 mg/kg/day (10 times the therapeutic dose) resulted in a slight increase in liver enzyme levels (ALT, AST), but no histopathological changes were observed in the liver or other organs[1]
4. Drug interactions: Lavoconazole It is a moderate inhibitor of human CYP3A4 (Ki = 0.5 μM), and when used in combination with CYP3A4 substrates (e.g., midazolam), it can increase plasma concentrations in healthy volunteers by 2-fold; no significant interactions with warfarin or digoxin were observed [2]. 5. Reproductive toxicity: In teratogenicity studies in rats and rabbits, no evidence of fetal malformation or embryotoxicity was shown at doses up to 50 mg/kg/day of lavoconazole [1].

[1]. In vitro and in vivo antifungal activities of ER-30346, a novel oral triazole with a broad antifungal spectrum.Antimicrob Agents Chemother. 1996 Oct;40(10):2237-42.

[2]. In vitro activity of a new oral triazole, BMS-207147 (ER-30346)Antimicrob Agents Chemother. 1998 Feb;42(2):313-8.

[3]. Efficacy of ER-30346, a novel oral triazole antifungal agent, in experimental models of aspergillosis, candidiasis, and cryptococcosis.Antimicrob Agents Chemother. 1996 Oct;40(10):2243-7.

Lavoconazole belongs to the triazole class of compounds, with the chemical name 1-butyl-1H-1,2,4-triazole, where the butyl group is substituted at positions 2, 2, and 3 with hydroxyl, 2,4-difluorophenyl, and 4-(p-cyanophenyl)-1,3-thiazolyl-2-yl groups, respectively (R,R stereoisomers). It exerts its antifungal activity by inhibiting 14α-demethylase, an enzyme involved in sterol synthesis, leading to fungal cell wall lysis and cell death. (NCIO4) Lavoconazole can be used as an ergosterol biosynthesis inhibitor, an antifungal drug, an EC 1.14.14.154 (sterol 14α-demethylase) inhibitor, and an anti-leishmaniasis drug. It belongs to the triazole, fluorobenzene, tertiary alcohol, 1,3-thiaazole, and nitrile classes of compounds. Lavoconazole is a triazole compound with antifungal activity. Lavoconazole inhibits 14α-demethylase (an enzyme involved in sterol synthesis), leading to fungal cell wall lysis and cell death. (NCI04)

---

Drug Indications
Studied for the treatment of fungal infections, aspergillosis, candidiasis, and onychomycosis.

---

In this study, BMS and ITR at a concentration of 1 μg/ml showed inhibitory activity against all but one of the 16 Aspergillus strains. Similarly, Hata et al. also observed consistent activity of BMS and ITR against Aspergillus strains. The anti-Aspergillus efficacy of BMS and ITR was comparable. Fluconazole (FLU) was ineffective against Aspergillus fungi. Buthiacromegaly toxin (BMS) and itraconazole (ITR) also showed fungicidal activity against 50% to 74% of the tested Aspergillus strains.
Compared to fluconazole, buthiacromegaly toxin and itraconazole showed significantly different activities against other filamentous fungi, while fluconazole was ineffective against most filamentous fungi. Itraconazole and buthiacromegaly toxin were effective against dermatophytes, while fluconazole showed lower activity against Microsporum gypseum. Fusarium stenocladus, Penicillium mutagenesis, and Penicillium fungi are sensitive to thiodicarboxamide and itraconazole. While both itraconazole and thiodicarboxamide are effective against most dark-skinned fungi, itraconazole appears to be slightly more active than fluconazole. Both thiodicarboxamide and itraconazole show low activity against most Pseudomonas boydii, Sporothrix schenckii, and Zygomycetes, and are generally ineffective against Fusarium fungi. Unlike Aspergillus, BMS and ITR have no fungicidal activity against other filamentous fungi. In summary, BMS is a novel triazole antifungal drug with 2 to 4 times the potency of ITR and 40 times the activity of fluconazole (FLU) against a wide range of fungi. Its antibacterial spectrum includes some fluconazole-resistant yeast strains. Similar to ITR, BMS has fungicidal activity against Cryptococcus and many Aspergillus strains. BMS’s in vitro antibacterial spectrum makes it a promising candidate for human treatment. [2]

---

1. Lavoconazole (ER-30346, BMS-207147) is a novel triazole antifungal drug jointly developed by Eisai Co., Ltd. and Bristol-Myers Squibb, aiming to overcome the limitations of existing azole drugs (e.g., narrow antibacterial spectrum, drug resistance)[1]
2. Mechanism of action: Lavoconazole inhibits fungal lanosterol 14α-demethylase (CYP51), which is a key enzyme in the biosynthesis of ergosterol (a major component of fungal cell membranes). Inhibition of CYP51 leads to ergosterol depletion and accumulation of toxic methylated sterols, which disrupt the integrity and function of fungal cell membranes, ultimately resulting in growth inhibition or cell death [2]. 3. Antifungal properties: Lavoconazole has a broader antifungal spectrum and higher efficacy than fluconazole and itraconazole, especially effective against Aspergillus and azole-resistant Candida strains; it has a long plasma half-life and high oral bioavailability, making it suitable for once-daily oral administration [3]. 4. Clinical development: Lavoconazole was evaluated in a phase II clinical trial for the treatment of invasive fungal infections (aspergillosis, candidiasis, cryptococcosis) in immunocompromised patients, and the results showed good efficacy and safety; however, due to the strategic decisions of pharmaceutical companies, its development has not entered phase III [1].

C22H17N5OF2S

437.46508

437.112

C, 60.40; H, 3.92; F, 8.69; N, 16.01; O, 3.66; S, 7.33

182760-06-1

Ravuconazole-d4;1329499-27-5

467825

Off-white to yellow solid powder

1.4±0.1 g/cm3

674.9±65.0 °C at 760 mmHg

362.0±34.3 °C

0.0±2.2 mmHg at 25°C

1.666

3.89

1

8

6

31

657

2

FC1=CC(F)=CC=C1[C@](CN2C=NC=N2)(O)[C@@H](C)C3=NC(C4=CC=C(C#N)C=C4)=CS3

OPAHEYNNJWPQPX-RCDICMHDSA-N

InChI=1S/C22H17F2N5OS/c1-14(21-28-20(10-31-21)16-4-2-15(9-25)3-5-16)22(30,11-29-13-26-12-27-29)18-7-6-17(23)8-19(18)24/h2-8,10,12-14,30H,11H2,1H3/t14-,22+/m0/s1

p-(2-((alphaR,betaR)-2,4-Difluoro-beta-hydroxy-alpha-methyl-beta-(1H-1,2,4-triazol-1-ylmethyl)phenethyl)-4-thiazolyl)benzonitrile

BMS 207147; BMS207147; BMS-207147; 182760-06-1; Ravuconazole [INN]; Benzonitrile, 4-[2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-thiazolyl]-; ER-30346 ;ER 30346 ; ER30346.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 50 mg/mL (~114.29 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.71 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 25.0 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: ≥ 2.5 mg/mL (5.71 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.

---

View More

Solubility in Formulation 3: ≥ 2.5 mg/mL (5.71 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.

---

Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (5.71 mM)

---

 (Please use freshly prepared in vivo formulations for optimal results.)