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10. Wang, T.; Ueda, Y.; Zhang, Z.; Yin, Z.; Matiskella, J.; Pearce, B. C.;
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________________________________________________________________________________
Oteseconazole (Vivjoa): A CYP51 Inhibitor
for Treating Recurrent Vulvovaginal
Candidiasis
Charles L. Lail III and
Timothy J. Hagen
1. Background
It is reported that around 9% of all women will develop recurrent vulvovaginal
candidiasis (RVVC) in their lifetime, with around 75% of women having at least one case
of vulvovaginal candidiasis in their lifetime.
Disease Control and Prevention (CDC) as the development of at least three cases of
vaginal yeast infections caused by a fungus from the genus Candida in a 12-month
period. RVVC has side effects of burning, itching, pain, and vaginal discharge.
Oteseconazole (1, Vivjoa) was developed by Mycovia Pharmaceuticals Inc. as a
breakthrough in the treatment of RVVC. Oteseconazole (1) was patented on August 18,
2020, and FDA approved on April 28, 2022.
Chemistry and Pharmacology of Drug Discovery, First Edition. Edited by Jie Jack Li.
© 2025 John Wiley & Sons, Inc. Published 2025 by John Wiley & Sons, Inc.
1,2
RVVC is defined by the Center for
3
Oteseconazole (1) is an orally administered
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150-mg pill. Functionally, oteseconazole (1) is a metalloenzyme-inhibitor that inhibits the
CYP51 enzyme that is found in most members of the genus Candida.
The standard drug used to treat Candida fungal infections before oteseconazole
(1) is fluconazole (14). Structurally, fluconazole (14) has a 1,2,4-triazole ring that is
responsible for its activity. Fluconazole (14) works quite well; however, there are many
species of Candida fungi that have developed resistance to fluconazole (14). Thus, there
is a continuing need for stronger treatment methods that remain highly potent and can
counter antibiotic resistance. Mycovia Pharmaceuticals sought to solve this problem by
using an extra nitrogen at position four in the azole ring, making oteseconazole (1) a
tetrazole. The tetrazole unit shows a marked selectivity for Candida albicans CYP51
over several of the common human CYP enzymes, something that had been a struggle for
previous generations of azole drugs (Figure
Chemistry and Pharmacology of Drug Discovery
1).
There are four major classes of antifungals available today: polyenes,
allylamines, echinocandins, and azoles. Each class acts through a different mechanism
and each class has its own strengths and weaknesses. The first group, the polyenes, was
Figure 1. Structure of nystatin (2) and amphotericin B (3)
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Chapter 6. Oteseconazole (Vivjoa)
started in 1951 with the discovery of nystatin (2). About 5 years later, a molecule known
as amphotericin B (3) was developed, which became the first broad spectrum antifungal
treatment. As the name implies, polyenes are distinguishable by structures, which contain
many conjugated double bonds. Nystatin (2) has six double bonds (with one single bond
breaking the conjugated chain) and amphotericin B (3) has seven conjugated double
bonds. The polyenes are typically applied intravenously due to their larger molecular
weights; nystatin (2) has a molar mass of 926.1 g/mol, while amphotericin B (3) has a
molar mass of 924.1 g/mol. The polyenes are commonly believed to complex directly to
ergosterol itself, thus interrupting the synthesis of molecules necessary for the
4–6
maintenance of plasma membranes.
This would lead to direct terminal lysis of the
fungal cells. The polyenes thus have a different mode of action to the other three
categories in that they do not inhibit a specific enzyme, rather, they inactivate the final
product of the ergosterol pathway. While the polyenes are beneficial due to their strong
broad-spectrum treatment properties, their drawbacks are the lack of oral bioavailability
and known nephrotoxicity associated with potassium wasting.
7
For these reasons,
amphotericin B (3) typically fits into the therapeutic arsenal as being the drug of choice
only in cases of severe, systemic fungal infections that could not be effectively treated by
drugs with more mild side effects (Figure
2).
The second group, the allylamines, was introduced in the late 1970s. The first of
the allylamines, naftifine (4), was patented in 1976.
functional group—a tertiary amine adjacent to an allyl group. The amine is typically
connected to a fused aromatic system, such as naphthalene, as in the structures of
naftifine (4) and terbinafine (5). Other ring systems than naphthalene have been
employed. The mode of action for allylamines is inhibition of squalene epoxidase.
the four major classes of antifungals, allylamines act the earliest in the ergosterol
synthesis pathway. The allylamines are generally quite orally bioavailable and can be
administered as oral pills.
12
h.
Allylamines have the distinct advantage of being both fungistatic and fungicidal, that
is, they both inhibit further growth of fungi and kill fungi.
generally avoid any interactions with cytochrome P450 and therefore have very few
Figure 2. Structure of naftifine (4) and terbinafine (5)
8
The allylamines all bear the same
11,12
In humans, the C
of terbinafine (5) is reached in under 2
max
13
The allylamines also
9,10
Of
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Chemistry and Pharmacology of Drug Discovery
drug–drug interactions.13 The primary downside of the allylamines is that they undergo
heavy metabolism which limits their effectiveness; for example, terbinafine (5) can be
12
3).
metabolized into 15 different metabolites, each of which is inactive (Figure
Figure 3. The structures of caspofungin (6) with molecular weight of 1093.31 g/mol, and
micafungin (7) with molecular weight of 1270.28 g/mol
The third group, the echinocandins, is the most recently developed class. They
have their beginning in 1992 with the development of caspofungin (6). The other popular
echinocandin is micafungin (7), developed in 2004 by Astellas Pharmaceuticals. They are
the only class of molecules out of the four that do not work inside of the ergosterol
synthesis pathway. Echinocandins are responsible for the noncompetitive inhibition of
the 1,3-βthe synthesis of 1,3-β-
D-glucan synthase enzyme. As the name implies, this enzyme is responsible for
D glucans. The 1,3-β-glucans are essential building blocks for the
structural integrity of cell walls. Fungal infections can actually be detected by elevated
14
levels of 1,3-β-glucans.
typically responsible for about 30–55% of the cell wall composition.
Most species of fungi have these glucans; 1,3-β-glucans are
15
Structurally
speaking, 1,3-β-glucans are polymers of glucose that are connected by a 1,3-linkage;
there is typically some branching off of the 6 position, but is not a requirement.
15
These
polymers are typically about 1,500 units long and are responsible for both the elasticity
16
and strength of the cell walls.
Echinocandins have used 1,3-β-glucans as a target
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Chapter 6. Oteseconazole (Vivjoa)
because they are simultaneously essential in fungi and completely absent in
16,17
mammals.
The echinocandins are not broad-spectrum antifungals. They are typically
quite good at treating fungi from Candida and Asperigillus but struggle against fungi
such as Cryptococcus neoformans.
spp., but are fungistatic against Asperigillus spp.
17,18
Echinocandins are fungicidal against Candida
19,20
The weakness of the echinocandins
is that, since they are so large, they are typically required to be administered as an
intravenous injection rather than the preferred model of an oral pill.
20
The last group, the azoles, is the largest group on the list. The azoles can be
roughly divided into generations depending on the number of nitrogen atoms in the ring.
The first generation of azoles utilized an imidazole ring, the second generation utilized a
triazole ring (usually a 1,2,4-triazole ring), and the most current azole drugs seem to be
utilizing tetrazole rings. The origin of azole drugs begins with the discovery of the mild
21
antifungal properties of benzimidazole, reported by D. W. Woolley in 1943.
He noted
the effect of benzimidazole and several substituted benzimidazole derivatives, such as
chlormidazole (8), against Saccharomyces cerevisiae. The next development occurred in
1959 when chlormidazole (8), a substituted benzimidazole, was developed and marketed
as a 5% topical ointment for antifungal treatment. This became the first drug developed
and sold as an azole antifungal.
22
The next advancement for azoles occurred in 1969
when three azole antifungals were reported: clotrimazole (9), miconazole (11), and
econazole (12).
22
Structurally speaking, miconazole (11) and econazole (12) are quite similar.
They are only different by miconazole (11) having an extra chlorine atom. Miconazole
(11) became the more popular of the two and is thus seen as the “parent compound” after
which structure many other azoles were developed. Both miconazole (11) and econazole
(12) are successful at treating superficial fungal infections of various types; however,
miconazole (11) can be used to treat systemic fungal infections, while econazole (12) is
bound too tightly by serum proteins to be useful against systemic fungal infections.
22
Drugs similar to miconazole (11) and econazole (12) include: dapaconazole, isoconazole,
tioconazole, fenticonazole, sertaconazole, sulconazole, and oxiconazole. Each of these
compounds can be synthesized from the intermediate 1-(2,4-dichlorophenyl)-2-(1Himidazol-1-yl)-ethanone. This intermediate compound is generally reduced from a ketone
to an alcohol, and the alcohol is then alkylated. Miconazole (11) and its derivatives are
usually marketed as racemic mixtures. Miconazole (11) had some early success as a
intravenously administered drug; however, its serum concentration was reported to
22
decrease rapidly.
In addition, the developers used a 10% solution of Cremophor EL® to
make the compound soluble; subsequently, there were toxicity concerns. There is still
debate over whether the toxicity was from miconazole (11) itself, or whether it was from
22–25
the Cremophor EL.
generally applied topically (Figure
Either way, miconazole (11) and each of its derivatives is
4).
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Chemistry and Pharmacology of Drug Discovery
Figure 4. First generation azoles chlormidazole (8), clotrimazole (9), flutrimazole (10),
miconazole (11), and econazole (12)
Clotrimazole (9) has a different structure compared to the miconazole (11)
derivatives. It still contains the imidazole moiety but has a central quaternary carbon that
is bonded to two phenyl rings and a 2-chlorophenyl ring. There is only one real derivative
of clotrimazole (9) named flutrimazole (10). As the prefix implies, flutrimazole (10) uses
fluorine instead of the chlorine from clotrimazole (9). Clotrimazole (9) managed slightly
better success than did the miconazole (11) derivates in that it has very good broad
spectrum activities that even rival those of amphotericin B (3).
22
Early data showed
clotrimazole (9) to be orally bioactive, however, fast metabolism in the liver and toxicity
26
concerns have limited clotrimazole (9) to a topical cream.
The biggest breakthrough for the first generation of azoles was the development
of ketoconazole (13) by Janssen Pharmaceutica in 1977. Ketoconazole (13) keeps the
imidazole and the 2,4-dichlorophenyl ring but makes major changes to the rest of the
molecule. First, the ether linkage is turned into a dioxolane ring, and then an N-acyl 4piperazinyl-phenyl substituent is attached to the dioxolane ring by an ether linkage.
Ketoconazole (13) is sold as a racemic mixture. The biggest achievement of ketoconazole
(13) is that it is orally bioactive against systemic fungal infections. This achievement
made ketoconazole (13) the “gold-standard” of azole drugs for nearly a decade.
Ketoconazole (13) has very broad-spectrum activity making it similar in properties to
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Chapter 6. Oteseconazole (Vivjoa)
miconazole (11); the only exception is that ketoconazole (13) is inactive against
22,25,27
Aspergillus.
Despite its major breakthrough of being the first azole to be orally
bioactive, the drug does have several negatives that have resulted in the assignment of a
black-box label from the FDA in June 2013.
28
The major short-comings of ketoconazole
(13) are: oral absorption varied widely on an individual basis and was dependent on pH,
an inability to cross the blood-brain-barrier, strong cases of hepatotoxicity, dosecorrelated reduction in testosterone and cortisol, and numerous drug–drug interactions
22–25,29
from inhibition of Cytochrome P450.
The next breakthrough in the development of the azoles comes with the
development of fluconazole (14) by Pfizer, which was given FDA approval in 1990.
Fluconazole (14) began the second generation of azoles, which uses 1,2,4-triazole rings
instead of imidazole rings. Fluconazole (14) represents a large increase in progress over
the imidazole-generation, particularly from a pharmacokinetic perspective. Fluconazole
(14) has around 100% oral absorption with about 90% oral bioavailability. Another
improvement over previous drugs is that 64% of fluconazole (14) clears the kidneys
30
unmetabolized and is excreted through the urine.
Its water solubility and bioavailability
have led fluconazole (14) to be an invaluable tool in the treatment of cryptococcal
meningitis.
23
Fluconazole (14) is also one of the least expensive antifungal drugs on the
market today. The downsides of fluconazole (14) are that it is not active against
filamentous fungi such as Aspergillus spp. and that there is an ever increasing amount of
23,26
resistance to fluconazole (14) treatment.
Fluconazole (14) is still one of the most
commonly prescribed antifungal drugs on the market today.
Voriconazole (15), also developed by Pfizer, was FDA approved in 2002. The
25,31
oral form of voriconazole (15) has equal bioavailability with fluconazole (14).
It has
good broad-spectrum activity including the treatment of pathogens from Candida,
Asperilligius, C. neoformans, and several types of mold pathogens such as Scedosporium
31,32
spp. Or Fusarium spp.
100× greater) against fluconazole (14)-resistant strands of C. albicans.
Voriconazole (15) has also demonstrated good activity (10–
31,32
Voriconazole’s (15) primary uses today are prophylactic treatment in stem-cell transfer
patients, and in the general treatment of Aspergillosis, against which it has actually
25,33
outperformed amphotericin B (3).
There are two primary downfalls of voriconazole
(15). First is its inhibition of three human CYP450 enzymes (2C9, 2C19, and 3A4) that
has caused problems.
25,32,34
Second, in addition to having similar side-effects as the other
azoles, voriconazole (15) uniquely bears side-effects such as skin reactions,
hallucinations, and mental confusion.
25,32
Voriconazole (15) is also highly metabolized by
the liver, with at least nine different metabolites being structurally confirmed; studies
31
have shown that only 5% of voriconazole (15) is excreted unchanged.
Voriconazole
(15) remains useful as it is able to treat several pathogens that are not treatable by other
antifungals, but the possible side effects must be carefully monitored.
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