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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5371_Библиотеки_им_академика_М_И_Перельмана
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Chemistry and Pharmacology of Drug Discovery
R2 and R6 as well. Noteworthy, this chapter focuses on renewing the structure-activity
relationships (SAR) related to ciprofol (1) by Qin’ work.
In 2014 and 2017, Qin and coworkers patented and published the design and
evaluation of ciprofol (1) as a promising anesthetic for head-to-head evaluation with
2
propofol (2) in detail, allowing us to directly clarify the effect of different groups in R
6
. As shown in Figure 4, a validated animal model of general anesthesia46 is measured by
R
and
loss of righting reflex (LORR) experiment, which is recorded in three periods (induction,
duration of anesthesia and recovery time), respectively. Using this LORR data, ED
(mg/kg, 50% of the mice to lose righting reflex, being like the HD
(mg/kg, median lethal dose), and HD
(mg/kg, the dose required to produce 10 min of
10 min
of James’ work), LD
50
50
50
anesthesia) are gained to evaluate the potency of 2,6-disubstituted phenol derivatives.
Figure 4. Loss of righting reflex (LORR) experiment
As shown in Table 3, 2-isopropyl was pre-introduced in one side chain of phenol
11
as a model class based in propofol (2).
increase the potency (ED
= 3.7 mg/kg) with N (the carbon number of both side
50
The displacement of cyclopropyl will significantly
chains) = 8 and (R)-configured enantiomer ciprofol (1) exhibits the highest potency with
the least HD
(4.8 mg/kg). Compound 6 containing a cyclopropyl group evidences a
10min
similar trend that (R)-enantiomer performs higher potency than the other isomers. Together,
configuration obviously has an influence on the ED
and LD50. Interestingly, more steric
50
hindrance including [5 (N = 9), 6 (N = 9), 7 (N = 10), 8 (N = 11)] decreases potency with
43
increasing the carbon number of chain, which is opposite to the trend of N 8.
≤
The SAR of the other side chain with cyclopropylethyl are shown in Table 4.11
No substitution (compound 9) brings a deep anesthesia but with long recovery time, which
means a great risk to surgical operations. Simple substitutions (Me-(10)/Et-(11)//OMe(12)) result in better potencies with similarly low ED
and shorter recovery time.
50
Additionally, compound 12, OMe results in reduced recovery time compared with
compounds 10 and 11. The introductions of more steric hindrance (1, 14–19) in the other
side chain seemly benefit in reduced ED
compared with propofol (2). However, most of
50
them cannot exhibit a quick recovery except (1, (R,R)-16 and (R,S)-16). Even though both
ciprofol (1) and (R,R)-16 exhibit lower ED
and HD50 compared with PF0713 (3), data of
50
duration and recovery time seemly are not improved. Besides, (R,R)-16 shows a better
profile than ciprofol (1), as well as GABA
receptor binding assay. Why is ciprofol (1) the
A
lucky one to be developed?
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Chapter 12. Ciprofol (Cipepofol)
Table 3. In vivo studies on sedation and SAR study of 2,6-disubstituted phenol
derivatives
Source: Adapted from Qin et al. 11
In vivo studies (Table 5), tested compounds are administered to fasted rat at
11
1 mg/kg intravenously (n = 3).
Both ciprofol (1) and (R,R)-16 show higher C
max
(maximum plasma concentration = 834, 713 ng/mL), lower CL (100, 95 mL/kg min) and
shorter T
= 42 min). Highest V
T
1/2
(28, 31 min) than propofol (2) (C
1/2
of propofol (2) demonstrates its high distribution into body
dss
= 384 ng/mL; CL = 204 mL/kg min;
max
tissues among them. Together, both ciprofol (1) and (R,R)-16 elicit superiority to systemic
exposure than propofol (2) according to
Qin’s study (Table 5). More importantly, no
significant differences are reported between ciprofol (1) and (R,R)-16. However, based on
the development of CMC (Chemical, Manufacturing, and Control), (R,R)-16 containing
two chiral carbon center appears to be the most difficult to develop, which may answer
why ciprofol (1) is the lucky one.
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Table 4. In vitro activity on sedation and SAR study of 2,6-disubstituted phenol
Chemistry and Pharmacology of Drug Discovery
derivatives
Source: Adapted from Qin et al. 11
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Table 5. Pharmacokinetic parameters of propofol (2), ciprofol (1) and (R, R)-16
Chapter 12. Ciprofol (Cipepofol)
Source: Adapted from Qin et al. 11
4. Pharmacokinetics and drug metabolism
In vivo study,35 ciprofol (1) demonstrates a dose-dependent increase (1, 2, or 4 mg/kg) in
exposure after intravenous injection (see Table
V
= 7.79 L/kg (rats) and 6.06 L/kg (dogs), higher than total fluid volumes. In rats, the
ss
concentrations in the adrenal gland, fat, skin, ovary, and kidneys are 5 times higher than
plasma concentrations. It also exhibits a good penetration ability in the blood–brain barrier,
detected to 3.2 times in brain tissues higher than that in plasma. The residual concentration
of ciprofol (1) is less than 10% of the peak concentration (C
administration, except in the fat, skin, bladder, and uterus. Interestingly, ciprofol (1) is
demonstrated to high binding rate to plasma proteins in rat, dog, and human species,
ranging from 85% to 96% within a concentration range of 80–1200 ng/mL.
6). It is easily distributed in the tissues with
) after 240 min of
max
Table 6. Pharmacokinetic parameters of ciprofol (1) after a single injection in male and
female rats/dogs
Source: Adapted from Liao et al. 35
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Chemistry and Pharmacology of Drug Discovery
In a Phase I study, a single dose of 0.4 mg/kg [14C] ciprofol (1) is administered
47
to six healthy subjects.
Being similar with propofol (88% in urine within 5 days and less
than 2% in feces),48 ciprofol (1) is primarily excreted through the urine (84.6% in 10 days)
and feces (2.65%). Besides, propofol was observed to be expelled through exhalation in
roughly equivalent to one billionth, indicating that ciprofol (1) could also be eliminated via
48
the same pathway.
(Figure
5). The metabolic pathways of ciprofol (1) in vivo are hypothesized to involve
It identifies twenty metabolites and the main metabolic pathways
oxidation, followed by glucuronidation and sulfation. The primary metabolite identified is
a conjugate of ciprofol (1) with glucuronic acid (M4) in both plasma and urine, which is
47
consistent with propofol (2).
The predominant metabolites found are M4, M2-4, M3, and
M5, which collectively represented 79.3% (plasma), 4.36% (plasma), 2.28% (urine), and
3.93% (plasma) of the total plasma and urine radioactivity, respectively. Additionally, a
small amount of M7, accounting for 0.18% of the overall plasma radioactive exposure,
plays an intermediate toward M2–4, M3, and M5. Provided by propofol (2), four similar
urinary metabolites were identified as the glucuronic acid conjugate of propofol (2, 53%)
and the glucuronic acid (18% & 13%) and sulphate (9%) conjugates of 2,6-diisopropyl-
48
1,4-quinol.
Typically, the metabolite formed through glucuronidation is widely regarded
as nonhypnotic and nontoxic.
Figure 5. Proposed main metabolic pathways of ciprofol (1) in humans. Source: Adapted
Another study investigating pharmacokinetic (PK) parameters of ciprofol (1) in
healthy subjects compared different administration models, including single-dose
administration, sequential maintenance administration after the initial dose, and
from Bian et al.
47
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Chapter 12. Ciprofol (Cipepofol)
maintenance dose after the loading dose.22 The results revealed the following PK
parameters at a single 0.4 mg/kg dose of ciprofol (1): C
1330.0 ng/mL; T
(time to reach C
max
): 2.0 min; Elimination half-life (T
max
Clearance (CL): 1.47 L/h/kg; Area under the curve (AUC
volume of distribution (V
): 4.3 L/kg; These PK parameters indicate a rapid onset of action
d
(maximum concentration):
max
): 2.09 h;
1/2
): 271.67 ng h/mL; Apparent
0–∞
and a short peak time after a single dose of ciprofol (1). Additionally, it exhibited a high
clearance and a small volume of distribution, aligning with the anticipated characteristics
of short-term intravenous anesthesia.
In contrast, when continuous infusions of ciprofol (1, 0.4–0.5 mg/kg/h) for 4 and
12 h are performed with propofol (2, 2.0 mg/kg/h) as the positive control in another study,
max
and T
both T
distribution.
are significantly prolonged, accompanied by an increased volume of
1/2
23
The plasma concentration-time profiles of ciprofol (1) exhibit similarity to
those of propofol (2), albeit with lower concentrations. Following the initial dose, both
ciprofol (1) and propofol (2) show a rapid increase in plasma concentration. After the
maintenance infusion dose, there is an initial decrease in plasma concentration for both
drugs, followed by a gradual increase over time.
However, differences of pharmacokinetic
(PK) parameters between ciprofol (1) and propofol (2) are complex in different studies. In
a Phase II study,18 drug exposure of propofol (2) is approximately 4 to 5 times higher than
that of ciprofol (1) at a low dosage. Ciprofol (1) exhibits slightly lower values for half-life
(T
) and volume of distribution compared to propofol (2), indicating a relatively shorter
1/2
duration of action and a more confined distribution in the body. T
and CL values of
max
ciprofol (1) are very similar to those of propofol (2), suggesting comparable rates of
absorption and elimination between the two drugs.
In human liver microsome incubations,35 CYP2B6 accounts for the major
metabolism isoform for ciprofol (1), followed by CYP1A2 and CYP2C19.
5. Efficacy and Safety
Ciprofol (1) is generally well tolerated in clinical trials.2 No evidence of reproductive
toxicity associated with ciprofol (1) has been observed in rat fertility and early embryonic
development toxicity tests, embryo-fetal developmental toxicity tests, and perinatal
developmental toxicity tests. Besides, all the results of Ames with Salmonella typhimurium
test, chromosome aberration test and mouse bone marrow micronucleus support negative
genotoxicity.
In beagle dogs,35 transient tachycardia can be monitored in all the ciprofol (1) (1,
2, or 4 mg/kg) and propofol (2) groups, especially with 169% increase reported in 4 mg/kg
of ciprofol (1), while there is no significant change in respiratory rate or tidal volume after
ciprofol
obviously affected, as well as blood pressure. No post-effects are observed after recovery.
about 10 times lower dosage was administrated in clinical studies,
(1) administration. The corrected QTcF intervals and body temperature will be
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Chemistry and Pharmacology of Drug Discovery
Multiple clinical trials present the strong evidence that low dosage ciprofol (1)
benefits patients from injection pain and incidence of AEs compared to 4–5 times higher
dosage of propofol (2). Interestingly, anesthesia-related seizures are common when
49
induction or relatively low concentration of an anesthetic drug.
Generally, increased γamino-butyric acid GABA-ergic inhibition, which exhibits totally opposite action of
mechanism of ciprofol (1) and propofol (2), can sensitize the cortex so that seizures occur
by a small amount of excitation. However, muscle fasciculation, as one of abnormal limb
movements, which may not be indicative of true seizures, was reported in the ciprofol (1)
group in a phase I clinical trial (33.3%
–0.4 mg/kg, 33.3%–0.6 mg/kg and 83.3%–
0.9 mg/kg). In a phase II a/b study, ciprofol (1) shows a lower incidence of muscle
14
fasciculation (4.5%, 2 patients of 42), without observed in the propofol (2).
One case of
myoclonus only in the ciprofol (1) group has been reported in a phase III trial of general
19
anesthesia induction in patients for elective surgery.
The incidence of epilepsy only in
the ciprofol (1) group was 3.8% (1 patients of 26) in a phase II trial of sedation in ICU
12
patients with mechanical ventilation, resulting in withdrawal from the trial.
The incidence
of body movement (patient has no conscious movement of the limbs) was higher in the
ciprofol (1) group than in the propofol (2) group (9.4% vs 0%) in anesthesia in
32
gynecological day surgery.
Additionally, a study for general anesthesia in patients
undergoing gynecological surgery reported two cases of body movement in propofol (2)
group (3.33%), which was
ascribed to injection pain.
50
The occurrence of seizures during
anesthesia might be observed at a rate of approximately 1 in every 172,592 administered
anesthetics according to studies of propofol (2), which may be influenced by factors such
as errors in administering anesthetic drugs, withdrawal of anti-epileptic medications, or a
lack of oxygen supply to the brain (cerebral anoxia) or an excessive buildup of carbon
49
dioxide (hypercarbia).
Since there is currently insufficient reliable evidence regarding the
relationship between ciprofol (1) and muscle fasciculation, it is essential to conduct further
research in the future.
There were no substantial indications of a drug-drug interaction between ciprofol
(1) and mefenamic acid.51 Mefenamic acid, which is known as an UGT1A9 inhibitor, was
demonstrated to have no significant effect on the pharmacokinetics and pharmacodynamics
of ciprofol (1) in healthy individuals when administered with mefenamic acid.
6. Synthesis
Sichuan Haisco Pharmaceutical Co. Ltd. developed and manufactured chemical process
and product development of ciprofol (1). As to date, the strategy to ciprofol (1) devised by
Haisco has diverted from drug discovery to drug development since the original disclosure
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Chapter 12. Ciprofol (Cipepofol)
was published in 2017.11 Here in this chapter, we disclosed four iterative routes reported
in two literatures.
Figure 6. Haisco synthesis route to ciprofol (1)
Developed by Qin’s work,
11
this initial route (A) in the drug discovery phase,
starts with the THP protection of phenol using pyridinium 4-toluenesulfonate (PPTS) to
afford 21 in 82.7% yield (Figure
accomplished by treating with n-BuLi and Weinreb amide in –20
6). A key ketone intermediate 23, a colorless oil, was
o
C then a direct
hydrolysis of crude oil and purified by flash chromatography in 78.3% yield. Noteworthy,
1.1 kg crude oil 23 was carried out in a telescopic reaction from 1.5 kg of 20 with general
52
work-up, which brings concerns about purification.
When treated with Grignard reagent,
ketone 23 was functionalized to alcohol 24 in 42% yield. A racemic (1) was obtained via a
two-step sequence of HSiEt
in CF3CO2H at −30 °C, followed by TBAF. A general chiral
3
resolution was carried out by chiral HPLC to afford R isomers, as known as ciprofol (1),
which was difficulty to achieve scale-up. Alternatively, an iterative process was reported
55
by Zhang et al.
from Haisco. Herein, the chiral resolution of ciprofol (1) was ultimately
achieved by recrystallizing the carbamate intermediate 25 which was obtained from the
reaction between (R)-(+)-1-phenylethyl isocyanate and racemic (1), followed by hydrolysis.
8
Earlier study showed (R)-(+)-1-phenylethyl was helpful to isolate PF0713 (3).
However,
the overall yield of the desired product was only 1–2% due to several challenges in this
route including the formation of complex impurities, which needs column chromatographic
purification or limited solid, and a low yield in 10% during the late-stage chiral resolution
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Chemistry and Pharmacology of Drug Discovery
step, the utilization of n-BuLi as well. Additionally, there were apprehensions regarding
the toxicity associated with the usage of PPTS for synthesizing the THP ether 21.
The route B is an improved process for intermediate 23 (see Figure 7). Zhang et
al. reported an iterative process for key intermediate 23 at the 100-gram scale.
52
Despite
having one fewer synthetic step, this route still posed a challenge in terms of purification
and lower yield. It necessitated a laborious column chromatographic purification process
to obtain the key intermediate 23. This purification step could potentially present
difficulties when attempting to scale up the process.
Figure 7. Haisco synthesis route B to ciprofol (1)
As shown in Figure 8 , route C by Zhang et al.52described a more practical
process using the same starting material 2-
sopropylphenol 20 on the kilogram scale. Under
I
the strongly basic conditions (NaOH) at 10–15 °C, the desired ether 28 was isolated in
95% yield, which was directly used to the next step without purification. Undergoing σ-
[3,3]-Claisen rearrangement reaction, 28 was converted to 29 in 53% yield in the presence
of K
2009 before.
with AlEt
. A similar strategy using Claisen rearrangement has been reported by Jenkins in
2CO3
53
Subsequently, a classic Simmons–Smith cyclopropanation was performed
(3 equiv)/CH2I2 (4 equiv) at 4 kg scale. The key racemic (1) was distilled to get
3
3.5 kg in 80% yield (96% purity), even though this cyclopropanation was slow and the
quenching conditions were severe and time-consuming. After racemic (1) was treated with
(R)-(+)-1-phenylethyl isocyanate/Et
N, three times recrystallizations from heptane
3
afforded carbamate 25 in 25% yield (97% purity, >99.5% de). However, despite
monitoring the water content in the reaction solution below 1.0%, a side reaction between
the isocyanate and water led to the formation of approximately 1–3% of urea.
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Chapter 12. Ciprofol (Cipepofol)
Figure 8. Haisco synthesis route C to ciprofol (1)
Finally, an endgame routine (Figure 9) was carried out by adjusting the priority
of carbamate reaction to increase one more solid 30 as an intermediate than route C,
developed by the same group.
whole process because of easily purification by recrystallizations and impurity control.
During the pilot plant synthesis, 29 was obtained followed with same condition of route C.
Then, an off-white solid 30 was easily afforded to 13.47 kg in 91% yield with 98% purity
when treated with (R)-(+)-1-phenylethyl isocyanate/Et
cyclopropanation was completely accomplished to get racemic 25 in the presence of
/CH2I2/CF3CO2H at room temperature at 11 kg scale, in which less loading of
ZnEt
2
CF
H than ZnEt2 could avoid the hydrolysis of 25 to racemic (1). Recrystallization
3CO2
afforded the optically pure 25 in 30−35% yield (99.4% de, and 99% HPLC purity). The
Figure 9. Haisco kilogram-scale route for clinical ciprofol (1)
52
Typically, much more intermediate solids will benefit the
N in heptane. Subsequently, the
3
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