Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5892_Библиотеки_им_академика_М_И_Перельмана
.pdf
128
https://t.me/med1917
Chemistry and Pharmacology of Drug Discovery
Itraconazole (16), a structural derivative of ketoconazole (13), was FDA
approved in 1992. It has broad-spectrum activity and is useful in the treatment of
aspergillosis, histoplasmosis and blastomycosis.
Torulopsis spp., and dematiaceous fungi.
25
11,35
It is also active against C. neoformans,
Itraconazole (16) has similar problems as
ketoconazole (13), in that its absorption is highly variable from person to person and
25
additionally reliant on the presence of food and the pH of the stomach.
The half-life of
itraconazole (16) also varies depending upon the dosage and the duration of the
treatment.
36
Another drawback is that the compound is so highly metabolized in the liver
that over 30 different metabolites have been reported, most of which are biologically
inactive.
11,27
Despite the heavy metabolism, itraconazole (16) has a much better safety
profile than most of the other azoles, with the exception of being contraindicated for
11,37
pregnant women.
Posaconazole (17), a structural derivative of itraconazole (16), was developed at
the Schering–Plough Research Institute. The chemists were working with a lead
compound and were surprised by abnormally high activity of one analog of their lead
compound. The researchers believed that an active metabolite of the compound was
responsible for better activity than the lead compound. This led to the development of
24,38
Posaconazole (17) in 2004.
The deviations in structure include the changing of the
1,3-dioxolane ring to a furan ring, replacing the 2,4-dichlorophenyl ring with a 2,4difluorophenyl ring, and the inclusion of an alcohol on the triazolone ring substituent.
Posaconazole (17) is another broad-spectrum antifungal drug. It has strong activity
31
against C. albicans, C. neoformans, and Aspergillus spp., among others.
Posaconazole
(17) specialized in the treatment of C. neoformans, against which it significantly
31
outperforms fluconazole (14) and amphotericin B (3).
Posaconazole (17) is both
fungistatic and fungicidal against C. neoformans. Posaconazole (17) shares the same
problems as ketoconazole (13) and itraconazole (16) in that absorptions varies widely
25
upon food intake and gastric pH.
It has low oral bioavailability (10–40%), and it is
primarily metabolized in 15–20 h by glucuronidation, although most of the drug passes
through the body unmetabolized.
(17) has linear pharmacokinetics.
34,39
Unlike most of the other azole drugs, posaconazole
39
Posaconazole (17) has a better safety profile than
voriconazole (15) and itraconazole (16). It avoids the intense metabolism problems of
itraconazole (16), and has much better interactions with the human CYP enzymes, with
25
5).
the exception of 3A4 (Figure
129
https://t.me/med1917
Chapter 6. Oteseconazole (Vivjoa)
Figure 5. The structures of ketoconazole (13) and 1,2,4-triazole drugs (14–17)
The third generation of azoles is the tetrazoles. The tetrazole ring has been
gaining popularity in its use in antifungal medications.
of the review, have chosen to use the tetrazole instead of the triazole, while other
antifungals have opted to add tetrazole rings in addition to the 1,2,4-triazole ring. The
primary advantage of the tetrazole antifungals is that the show marked selectivity
between antifungal CYP51 and human CYP enzymes, specifically CYP3A4, which is
typically an area of strong inhibition for the azole antifungals.
One of the most frequently mentioned problems with the azole class when
compared to the polyenes, allylamines, and echinocandins, is that the azoles typically
inhibit several of the human CYP450 enzymes. This generally leads to a laundry list of
contraindications as to which other drugs they may not be co-administered with. As
40
Some drugs, such as the subject
24,41
Micafungin
(7)
42–44
Miconazole
(11)
42–44
Ketoconazole
(13)
45
130
https://t.me/med1917
Chemistry and Pharmacology of Drug Discovery
fungal infections tend to happen in patients who are already diseased, this represents a
significant flaw with the azole class. Below is a table that shows the degree of
interference with 6 CYP enzymes caused by several antifungal drugs. The azoles are
typically active against 2C9, 2C19, and especially active against 3A4. This is one area
that oteseconazole (1) will look to significantly improve upon (Table
1).
Inhibitor Class 1A2 2C9 2C19 2D6 2E1 3A4
Echinocandin None None None None None 13.5
Azole –
2.9 2 0.33 6.46 >10 0.07
Imidazole
Azole –
13 >100 28 17 90 0.2
Imidazole
Fluconazole (14)
42–44
Azole –
None 30.3 12.3 None None 13.1
Triazole
Voriconazole (15)
42–44
Azole –
None 8.4 8.7 None None 10.5
Triazole
Itraconazole (16)
42–44
Azole –
None >10 >10 None None 0.03
Triazole
Table 1. A summary of human CYP450 enzyme inhibition of several antifungal drugs.
All values are IC
(μM)
50
In summary, there are only four main classes of antifungal drugs. Each group
has specific pros and cons. All four categories work by targeting structural molecules
responsible for the formation and maintenance of cell walls or plasma membranes.
Polyenes are the best broad-spectrum compounds but have toxicity concerns and are not
orally bioavailable. Allylamines are orally bioavailable and have much lower drug–drug
interactions, but suffer from rapid, inactivating metabolism. Echinocandins are specific in
their treatment of fungi but are not orally bioavailable. Finally, azoles are generally orally
bioavailable and are fairly broad-spectrum, but have been known to cause drug–drug
interactions by off-site inhibition of Cytochrome P450. Oteseconazole (1) was designed
as an azole drug that would be both orally bioavailable and have much fewer drug–drug
interactions. It is less broad-spectrum than other azoles but is much more specific than
the previous imidazoles and triazoles.
2. Pharmacology
Oteseconazole (1) is a metalloenzyme inhibitor that targets the Candida CYP51 enzyme.
The CYP51 enzyme, which belongs to the cytochrome P450 monooxygenase
superfamily, is a sterol 14α-demethylase enzyme, meaning that its primary function is to
131
https://t.me/med1917
Chapter 6. Oteseconazole (Vivjoa)
catalyze the stereo- and regio-selective removal of a methyl group at position 14 of the
46,47
lanosterol chemical scaffold.
CYP51 removes a methyl group from lanosterol (18) to
form 4,4-dimethyl-5α-cholesta-8,14,24-trien-3ß-ol (19), which is abbreviated FF-MAS
(follicular fluid meiosis-activating sterol). FF-MAS (19) will undergo
eight further
reactions by a total of nine different enzymes to become cholesterol (20) in mammals and
48
ergosterol (21) in fungi.
Mutation of the erg11 gene that encodes for CYP51 has shown
a buildup of 14α-methyl-ergosta-8,24(28)dien-3β,6α-diol later down the enzymatic
pathway. This diol has been shown to be toxic to fungal cells (Figure
6).
48
Figure 6. The function of CYP51 is to catalyze the stereo- and regio-selective removal of
the methyl group at position 14. From there, cells can redox the structure into a number
of steroid derivatives such as cholesterol (20) in mammals and ergosterol (21) in fungi
Cholesterol and ergosterol have long been known to be key components of
cellular membranes. Sterols have been shown to primarily govern the fluidity and
permeability of the cellular membranes.
attractive target in the treatment of fungal diseases.
Oteseconazole (1) uses its tetrazole ring to bind to the heme atom of the CYP51
enzyme. The nitrogen atom at the 4-position of the tetrazole ring is responsible for
48
This makes the CYP51 enzyme a very
47
132
https://t.me/med1917
coordinating to the iron atom of the CYP51 enzyme. The heme atom generally
participates in the electron transfer process by varying its oxidation state. The
coordination of the basic nitrogen atom to the Lewis acid iron severely limits the iron’s
ability to switch oxidation state (Figure
Chemistry and Pharmacology of Drug Discovery
7).
Figure 7. The proposed step-wise mechanism of CYP51
24,47
3. Structure–Activity Relationship (SAR)
The development of oteseconazole (1) began by using the structure of voriconazole (15)
and optimizing each structural region. The first area to be optimized was the metalbinding group (MBG). The MBGs were evaluated for heme affinity with an in silico
model. Each MBG group was optimized using the PM3 method and geometry optimized
in the heme-bound position. The enthalpy values for each MBG group were calculated,
but not reported in the literature. Several MBGs were chosen to take into chemical
synthesis based upon their predicted affinity with the heme iron atom. The developers
were clear that they wanted groups that demonstrated high affinity for the heme iron but
did not have too high affinity for the iron. This choice was intended to avoid as many
nonspecific interactions as possible. A total of five compounds (24–28) were synthesized
with different MBGs using the chemical structure of voriconazole (15) as a starting
scaffold. Each compound in the SAR was evaluated based upon its MIC
against C. albicans and its IC
molecule against each of the common CYP enzymes that are responsible for drug–drug
interactions, CYP3A4 was chosen as a representative due to its history of strong
interactions with common azole drugs. The best MBG was the 1-imidazole 27. However,
(μM) against human CYP3A4. Instead of screening every
50
(μg/mL)
50
133
https://t.me/med1917
Chapter 6. Oteseconazole (Vivjoa)
it was not further utilized because it was mildly basic (pKa = 6.8) and it showed high
amounts of human CYP3A4 inhibition (IC
selected for further study due to its low basicity (pK
CYP3A4 inhibition (IC
= 32 μM) (Table 2).
50
= 0.8 μM). The 1-tetrazole group 25 was
50
= –1.1) and its low levels of human
a
No. R group MIC50 C.
albicans
a
IC50
CYP3A4
b
ratio
c
Selectivity
24 1-(1,2,3-Triazole) >16 8.0 0.5
25 1-Tetrazole
1 32 32
26 4-(1,2,4-Triazole) >16 51 3.2
27 1-Imidazole
0.5 0.8 1.6
28 2-Tetrazole 8 46 5.8
Table 2. All SAR information taken from Hoekstra et al.49
a
Units are μg/mL
b
c
Ratio is equal to IC50 CYP3A4/MIC50 C. albicans
Units are μM
The next portion of the SAR uses the tetrazole ring as its MBG and optimizes
the 3-fluoropyrimidine ring. In addition to changing the ring, the methyl group was
replaced with a difluoromethyl linker fragment that is more metabolism resistant. The 3fluoropyrimidine ring was changed to a 2,5-disubstituted pyridine ring for compounds
29–31. These compounds gave a slight increase in potency while demonstrating much
better selectivity than the 3-fluoropyrimidine ring, by comparison of structures 25 and 29.
As a point of clarity, compounds 29–34 were tested as racemic mixtures. A homology
docking model based on the structure of Trypanosoma cruzi highlighted a tyrosine
residue that could provide a favorable π-interaction if an aromatic group were placed in
the 5-position of the pyridyl ring. This gives rise to compounds 32–34. The additional
phenyl group was good increases to both the potency and the selectivity. The best
compound from the second phase was the racemic compound 34 (Table
3).
134
https://t.me/med1917
Chemistry and Pharmacology of Drug Discovery
No. R group MIC50 C. albicansa IC50 CYP3A4b Selectivity ratioc
29 H
0.25 136 544
30 Cl 0.25 74 296
31 OCH2CF3 0.06 72 1200
32 4-F-Ph 0.016 53 3313
33 4-CN-Ph ≤0.016 16 1000
34 4-CF3-Ph ≤0.016 >60 3750
Table 3. All SAR information taken from Hoekstra et al.49
a
Units are μg/mL
b
c
Ratio is equal to IC50 CYP3A4/MIC50 C. Albican
Units are μM
The third phase of the SAR, compounds 35-37 and 1, re-institutes the same
stereochemistry as the voriconazole (15) starting scaffold with respect to the alcohol and
the MBG. Each compound in this last group was synthesized as a racemic mixture, and
then separated via chiral chromatography. The single enantiomer 35 gave decisively
better results than did the racemic mixtures 34. Note the increase in both activity and
selectivity between compounds 34 and 35. Compounds 35–37 and 1 were more potent
than 32–34 and featured selectivity profiles that were much better than any previous
compounds. The idea for the ether group in compounds 37 and 1 came from the
homology model, which showed a serine residue toward the meta/para positions of the
phenyl ring. An ether group was added in the para position to hydrogen bond with the
serine residue. Compounds 37 and 1 were the best compounds in the Table
4 with low
MIC50 values and excellent selectivity for C. albicans CYP51 over the human CYP3A4.
Compound 1 was chosen over 37 due to three reasons. First, compound 37
showed inhibition of human CYP2C9 (IC
= 99 μM) and CYP2C19 (IC50 = 72 μM) in
50
addition to the CYP3A4 data. Second, 1 was extremely resistant to general liver
metabolism. The researchers incubated 1 with both human and animal liver microsomes
for 2 h and recovered 99% of compound 1. The oral-half life in humans was also found to
be >>24 h. Third, 1 was found to be orally efficacious from dosing in mouse and guinea
pig testing.
135
https://t.me/med1917
Chapter 6. Oteseconazole (Vivjoa)
No. R group MIC50 C. albicansa IC50 CYP3A4b Selectivity ratioc
35 CF
≤0.001 54 54,000
3
36 Cl ≤0.001 36 36,000
37 OCF3 ≤0.001 79 79,000
1 OCH2CF3 ≤0.001 65 65,000
Table 4. All SAR information taken from Hoekstra et al.49
a
Units are μg/mL
b
c
Ratio is equal to IC50 CYP3A4/MIC50 C. albicans
Units are μM
4. Pharmacokinetics and Drug Metabolism
Considering that oteseconazole (1) is a drug that is intended to treat recurring fungal
infections, it is beneficial that oteseconazole (1) is extremely resistant to general liver
metabolism. Preclinical data showed that when oteseconazole (1) was incubated with
both human and animal liver microsomes for 2 h over 99% of the starting material was
recovered completely un-metabolized.
half-life of approximately 138 days in humans.
49
Oteseconazole (1) is reported to have a human
50
During Phase 3 clinical trials, the
average blood plasma concentrations were found: 1396.9 μg/L at the end of Week 2
(induction period), 2679.3 μg/L at the end of Week 14 (maintenance period), and 873.4
51
μg/L by week 50 (end of study).
52
dose size.
the C
At the end of the maintenance period (week 14), the C
is 2.53 μg/mL. The AUC
min
The median t
is 64.2 h
24 h
with a high-fat, high-calorie meal (800–1000 Calories; 50% fat) the C
45% and the AUC
is increased by 36%.50 Several of the previous azole antifungal
0–72 h
is approximately 4–5 h, depending on
max
is 2.78 μ/mL, while
μg/mL.
50
If oteseconazole (1) is consumed
max
max
is increased by
drugs possessed a similar ability. There was no difference observed when oteseconazole
(1) was consumed with a low-fat, low-calorie meal. Oteseconazole (1) is primarily
excreted through feces (56%) and secondarily through urine (26%). There was no
difference in the pharmacokinetic profile regarding sex, race/ethnicity or mild to
50
moderate renal impairment. Oteseconazole (1) is not a P-glycoprotein (Pgp) substrate.
Oteseconazole (1)
MIC
50
(μg/mL)
Fluconazole (14)
MIC
50
(μg/mL)
136
https://t.me/med1917
Chemistry and Pharmacology of Drug Discovery
5. Efficacy and Safety
5.1. Efficacy
The third phase of clinical trials directly compared the efficacy of oteseconazole (1) to
fluconazole (14) and placebo. The study was conducted on 219 women with a history of
vulvovaginal candidiasis infection at 38 different sites within the United States.
patients were randomly split into two groups in a 2:1 ratio, with the larger group taking
oteseconazole (1). The larger group was induced with oteseconazole (1) according to the
following dosing regimen: on Day 1 consume 600 mg and on Day 2 consume 450 mg.
The smaller group was induced with fluconazole (14) according to the following dosing
regimen: on Days 1, 4, and 7 consume 150 mg of fluconazole (14). Following the
induction phase, the maintenance phase for the oteseconazole (1) group consisted of
taking 150 mg of oteseconazole (1) once per week for 11 weeks. The maintenance phase
for the fluconazole (14) group consisted of taking 150 mg of placebo once per week for
11 weeks. No drugs were administered after the eleventh week. The patients were then
monitored until the end of week 50 (Tables
Oteseconazole (1) Fluconazole (14)/Placebo
Resolution of current VVC
infection after Day 14
Occurrence of VVC infection
during maintenance period
Table 5. Efficacy of oteseconazole (1) in Phase 3 Clinical Trials51
5 and 6).
93.2% 95.8%
5.1% 42.2%
51
The
Isolate (# occurrences)
Candida albicans (266) 0.004 0.25
Candida glabrata (42) 0.030 2.00
Candida parapsilosis (19) 0.008 0.25
Candida tropicalis (11) 0.008 0.50
Table 6. MIC50 of oteseconazole (1) and fluconazole (14) against clinical isolates51
As another source of direct comparison between oteseconazole (1) and
fluconazole (14), during the Phase 3 Clinical Trials, researchers isolated the specific
strains of fungal infection that occurred during the maintenance period. They then
determined the MIC
the isolated fungal strains. Oteseconazole (1) was between 31- and 67-times more
effective against these isolates than fluconazole (14).
(μg/mL) of oteseconazole (1) and fluconazole (14) directly against
50
137
https://t.me/med1917
Chapter 6. Oteseconazole (Vivjoa)
5.2. Safety
The use of oteseconazole (1) is contraindicated in three groups of people: (1) females of
reproductive potential, (2) pregnant and lactating women, and (3) patients with known
hyper-sensitivity to oteseconazole (1).
an additional three groups of people: (1) those with renal impairment (with or without
dialysis), (2) those with hepatic impairment, and (3) those who are using breast cancer
resistance protein substrates (BCRPSs).
50
Further, oteseconazole (1) carries warnings for
6. Synthesis
The first reported synthesis of oteseconazole (1) is a five-step pathway by Hoekstra et al.
in 2014.
in the presence of copper and DMSO to achieve an 81% yield of compound 39. The next
step is addition of 2,4-difluorobromobenzene 40 with n-butyl lithium at –70 °C for 2 h.
This provided compound 41 in 43% yield. Compound 41 was then treated with
methyldiazenide at 0 °C and allowed to warm to room temperature. This solution was
then stirred for 2 h to afford compound 42 in 59% yield. Compound 42 then underwent
Suzuki coupling with 4-(2,2,2-trifluoroethoxy)phenylboronic acid 43 in the presence of
sodium carbonate using Pd(dppf)Cl
product 44 was obtained in 71% yield. This compound was then reacted directly with 1Htetrazole 45 in the presence of potassium carbonate to obtain a racemic mixture of
compound 1 in 29% yield. Chiral chromatography was employed to provide the pure
compound 1 (Figure
49
It begins by reacting ethyl difluorobromoacetate with 2,5-dibromopyridine 38
as catalyst. After 4 h under argon at 75 °C, the
2
8).
Соседние файлы в папке Библиотека им академика М.И. Перельмана