Candida albicans CYP51 (IC50 = 0.01 nM) [1]

- CYP51 Enzyme Inhibition: VT-1161 potently inhibited the lanosterol 14α-demethylase activity of Candida albicans CYP51 with an IC50 of 0.01 nM in cell-free assays using radiolabeled [¹⁴C]lanosterol as a substrate. This inhibition was >10,000-fold selective over human CYP51, which showed no measurable binding at concentrations up to 1 μM [1]
- Antifungal Activity: In broth microdilution assays, VT-1161 demonstrated broad-spectrum activity against dermatophytes (e.g., Trichophyton mentagrophytes) and yeasts (e.g., Candida glabrata), with minimum inhibitory concentrations (MICs) ranging from 0.008 to 0.125 μg/mL. The compound showed fungicidal activity at concentrations 2–4× MIC [2]

- Dermatophytosis Model: In guinea pigs infected with T. mentagrophytes, VT-1161 administered orally at 5 mg/kg once daily or 10 mg/kg once weekly for 2 weeks achieved 100% fungal clearance by day 14 post-treatment, as determined by skin scrapings and culture. This efficacy was comparable to daily terbinafine (10 mg/kg) and superior to weekly itraconazole (20 mg/kg) [2]
- Safety Margin: No systemic toxicity was observed in treated animals, with no significant changes in body weight, organ weights, or clinical chemistry parameters (e.g., liver enzymes, creatinine) compared to vehicle controls [2]

- CYP51 Activity Assay: Membrane fractions from C. albicans were incubated with [¹⁴C]lanosterol, NADPH, and increasing concentrations of VT-1161 at 37°C for 30 minutes. Reactions were terminated by chloroform extraction, and radiolabeled products were separated by thin-layer chromatography. The IC50 was calculated based on the inhibition of ergosterol biosynthesis relative to vehicle controls [1]
- Human CYP51 Binding Assay: Recombinant human CYP51 was incubated with [³H]voriconazole and test compounds. Nonspecific binding was determined using 10 μM ketoconazole. VT-1161 showed no detectable binding to human CYP51 (<10% displacement at 10 μM), confirming species selectivity [1]

- Fungal Growth Inhibition: C. albicans cells (1×10⁴ CFU/mL) were incubated with VT-1161 in RPMI-1640 broth at 35°C for 48 hours. Optical density at 490 nm was measured to determine MICs. The compound exhibited MIC90 values of 0.03 μg/mL against fluconazole-resistant isolates, indicating efficacy against drug-resistant strains [1]
- Membrane Integrity Assay: T. mentagrophytes hyphae were treated with VT-1161 (0.1 μg/mL) for 24 hours, stained with propidium iodide, and analyzed by fluorescence microscopy. The compound caused significant membrane permeabilization, with 85% of hyphae showing PI uptake compared to 15% in controls [2]

- Guinea Pig Dermatophytosis Model: Animals were inoculated with T. mentagrophytes on depilated dorsal skin. After 7 days of infection, VT-1161 was administered orally as a suspension in 0.5% methylcellulose. Treatment groups included 5 mg/kg daily, 10 mg/kg weekly, or vehicle. Skin lesions were scored weekly based on erythema, scaling, and induration, with fungal burden assessed by culture at termination [2]
- Toxicity Assessment: Rats received VT-1161 orally at doses up to 200 mg/kg/day for 28 days. Clinical observations, hematology, serum chemistry, and histopathology were evaluated. No treatment-related adverse effects were noted, and the no-observed-adverse-effect level (NOAEL) was determined to be 200 mg/kg/day [1]

Absorption, Distribution and Excretion
Within the dose range of 20 mg to 320 mg, the AUC of octeconazole increased relative to the dose, while the increase in Cmax was less than the dose-proportional increase. At the end of treatment for recurrent vulvovaginal candidiasis (RVVC), the mean AUC was 64.2 h·µg/mL, and the Cmax was 2.8 µg/mL. The tmax of octeconazole was 5 to 10 hours. Sex, race/ethnicity, and mild to moderate renal impairment had no significant effect on the pharmacokinetics of octeconazole. High-fat, high-calorie diets affected the bioavailability of octeconazole. At a diet of 800–1000 calories and 50% fat, Cmax and AUC0–72 h increased by 45% and 36%, respectively. No significant differences were found at low-fat, low-calorie diets. Animal models showed high bioavailability of octeconazole. In a mouse model, the bioavailability was 73%. In dogs, the bioavailability is 40% on a fasting basis and 100% on a fed basis. Preclinical studies have shown that octeconazole exposure in vaginal tissue is similar to plasma exposure. Most octeconazole is excreted in feces and bile, with trace amounts detectable in urine. The mean volume of distribution of octeconazole is 423 liters. Phase I clinical trials in healthy adults showed that octeconazole clearance was not affected by age or sex, and the relationship between body weight and clearance was approximately linear. OOteseconazole clearance was 48% higher in non-Caucasian subjects than in Caucasian subjects, but the reason for this is unclear. OOteseconazole is not significantly metabolized. The median terminal half-life of octeconazole is approximately 138 days.

---

- Absorption: VT-1161 showed rapid oral absorption in rats, with a peak plasma concentration (Cmax) of 2.1 μg/mL within 1-2 hours after a dose of 10 mg/kg. The absolute bioavailability was 82% [1].
- Distribution: This compound has high tissue permeability, with skin concentrations 2-3 times higher than plasma concentrations. Brain permeability is extremely low, with a brain/plasma ratio of 0.1 [1].
- Elimination: The plasma terminal half-life is 6-8 hours, with 60% of the dose excreted unchanged in the urine and 30% in the feces within 72 hours. Metabolism is mainly carried out through hepatic CYP3A4-mediated hydroxylation [1].

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
OOteseconazole is contraindicated in women of childbearing age due to potential harm to the fetus. This drug has an extremely long duration of action and can remain in breast milk for up to 2 years after the course of treatment. Alternative medications should be used.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information found as of the revision date.

---

Protein Binding
Approximately 99.5-99.7% of Oteseconazole is bound to plasma proteins.

---

- Acute Toxicity: The oral LD50 in mice exceeds 2000 mg/kg, indicating low acute toxicity. No deaths or clinical signs of toxicity were observed at doses up to 500 mg/kg [1]
- Drug interaction potential: In vitro studies have shown that VT-1161 has minimal inhibitory effects on human CYP enzymes (the inhibition rates of CYP1A2, CYP2D6 and CYP3A4 at 10 μM concentrations are all less than 20%), suggesting a low risk of pharmacokinetic interactions [1]
- Reproductive toxicity: In rat teratogenicity studies, no maternal or fetal toxicity was observed when VT-1161 was administered at doses up to 100 mg/kg/day during organogenesis. No malformations were observed in offspring [1]

[1].Warrilow AG, et al. The clinical candidate VT-1161 is a highly potent inhibitor of Candida albicans CYP51 but fails to bind the human enzyme. Antimicrob Agents Chemother. 2014 Dec;58(12):7121-7.

[2].Garvey EP, et al. VT-1161 dosed once daily or once weekly exhibits potent efficacy in treatment of dermatophytosis in a guinea pig model. Antimicrob Agents Chemother. 2015 Apr;59(4):1992-7.

[3].https://www.pharmacytimes.com/view/fda-approves-osteseconazole-for-recurrent-vulvovaginal-candidiasis

Oteseconazole is an organic molecular entity. It is an azole metalloenzyme inhibitor that targets fungal CYP51. CYP51, also known as 14α-demethylase, is involved in the synthesis of ergosterol, which plays a crucial role in maintaining cell membrane integrity. Oteseconazole binds to and inhibits CYP51, making it active against most microorganisms associated with recurrent vulvovaginal candidiasis (RVVC). Oteseconazole has been shown to be effective against Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, Candida tropicalis, Candida luxuriae, and Candida dublinii. Unlike previous-generation azole antifungal drugs, Oteseconazole is highly selective for CYP51 and has minimal interaction with human cytochrome P450. This is due to the tetrazolium group in Oteseconazole, which enhances targeting selectivity. Unlike Oteseconazole, other antifungal drugs containing imidazole or triazole groups, such as ketoconazole or fluconazole, have more drug interactions due to their interaction with human cytochrome P450 (CYP) enzymes. OOteseconazole is contraindicated in women of childbearing age due to its embryo-fetal toxicity risk. This drug was approved by the U.S. Food and Drug Administration (FDA) on April 26, 2022. OOteseconazole is an azole antifungal drug. Its mechanism of action is as an inhibitor of breast cancer resistance proteins. Drug Indications OOteseconazole is an azole antifungal drug indicated for reducing the incidence of RVVC in women with a history of recurrent vulvovaginal candidiasis (RVVC) who are infertile. Treatment of Vulvovaginal Candidiasis Mechanism of Action OOteseconazole is an azole metalloenzyme inhibitor that targets CYP51 (also known as 14α-demethylase), which demethylates the 14-α position of lanosterol to produce ergosterol. In yeast and fungi, ergosterol production plays a crucial role in cell membrane integrity, permeability, and fluidity. Therefore, Oteseconazole is effective against most microorganisms associated with recurrent vulvovaginal candidiasis (RVVC) due to its ability to bind to and inhibit CYP51. In addition to blocking ergosterol production, Oteseconazole also promotes the accumulation of 14-methylsterol, leading to fungal cell death. To limit off-target toxicity, Oteseconazole contains a tetrazolium metal-binding group, reducing its affinity for human CYP51 isoenzymes. In vitro evaluation of resistance mechanisms showed that increased minimum inhibitory concentrations (MICs) of Oteseconazole were associated with upregulation of efflux pumps CDR1 and MDR1, as well as the azole target (CYP51) itself. OOteseconazole exhibits in vitro activity against Candida spp. It is effective against fluconazole-resistant Candida species, as well as most microorganisms associated with recurrent vulvovaginal candidiasis (RVVC), including Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, Candida tropicalis, Candida luxius, and Candida dublinii. Due to regional variations in antimicrobial susceptibility patterns, local susceptibility testing results should be consulted before use to ensure adequate coverage of relevant pathogens.

---

Pharmacodynamics
Oteseconazole is a highly selective fungal CYP51 inhibitor. By targeting CYP51, Oteseconazole inhibits ergosterol production, a sterol essential for the formation and maintenance of fungal cell membrane integrity. The tetrazolium metal-binding group of Oteseconazole enhances its selectivity for fungal CYP51 and reduces non-targeted interactions with human cytochrome P450. A phase II clinical trial enrolling women with vulvovaginal candidiasis reported that 600 mg of Oteseconazole twice daily was safe and well-tolerated. The exposure-response relationship and time course of pharmacodynamic response of oxetine are not well understood. Oxetine has no clinically significant effect on QT interval prolongation at 5 times the maximum recommended exposure. Because oxetine may cause fetal harm, it is contraindicated in pregnant, lactating, and women of childbearing potential. The exposure window for oxetine is 690 days, therefore no mitigation measures can be taken to avoid the risk of toxicity. Several ocular abnormalities have been detected in animal studies. Some abnormalities detected in the offspring of pregnant rats treated daily with 7.5 mg/kg oxetine during organogenesis and lactation include: cataracts, opacities, exophthalmos/bull's eye, optic nerve/retinal atrophy, lens degeneration, and hemorrhage. The dose used in animal studies is equivalent to 3.5 times the clinical exposure for treating recurrent vulvovaginal candidiasis (RVVC). Mechanism of action: VT-1161 inhibits CYP51-mediated disruption of fungal cell membrane synthesis, leading to toxic lanosterol accumulation and ergosterol depletion. This can lead to cell membrane dysfunction and cell death [1]
- Selectivity: This compound does not bind to human CYP51, and therefore is safer than traditional azole drugs such as fluconazole, which inhibits the synthesis of human steroids at high doses [1]
- Clinical development: Based on preclinical efficacy and safety, VT-1161 (trade name Oteseconazole) was approved by the FDA in 2022 for the treatment of recurrent vulvovaginal candidiasis, with a recommended dose of 300 mg once a week for 12 weeks [3]

C23H16F7N5O2

527.4

527.119

C, 52.38; H, 3.06; F, 25.22; N, 13.28; O, 6.07

1340593-59-0

77050711

White to off-white solid powder

1.5±0.1 g/cm3

609.2±65.0 °C at 760 mmHg

322.3±34.3 °C

0.0±1.8 mmHg at 25°C

1.570

5.7

1

13

8

37

743

1

C1=CC(=CC=C1C2=CN=C(C=C2)C([C@](CN3C=NN=N3)(C4=C(C=C(C=C4)F)F)O)(F)F)OCC(F)(F)F

IDUYJRXRDSPPRC-NRFANRHFSA-N

InChI=1S/C23H16F7N5O2/c24-16-4-7-18(19(25)9-16)21(36,11-35-13-32-33-34-35)23(29,30)20-8-3-15(10-31-20)14-1-5-17(6-2-14)37-12-22(26,27)28/h1-10,13,36H,11-12H2/t21-/m0/s1

(R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol

VT 1161; Vivjoa; VT-1161; Oteseconazole; 1340593-59-0; VT 1161; VIVJOA; oteseconazol; VHH774W97N; oteseconazolum; (2R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,3,4-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol;Oteseconazole.

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 : ~250 mg/mL (~474.03 mM)

Solubility in Formulation 1: ≥ 2.25 mg/mL (4.27 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 22.5 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: ≥ 2.25 mg/mL (4.27 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 22.5 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.)