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________________________________________________________________________________
Ciprofol (Cipepofol): A γ-Aminobutyric Acid
Receptor Agonist for Induction of Anesthesia
Ji Zhang and
Dao-Qian Chen
Today’s anesthetic agents are mainly divided into inhalational agents and intravenous
agents based in drug administration,
flurane (
propofol, barbiturates (
diazepam), and etomidate.
Cipepofol, formerly HSK3486) was approved to indications including sedation in
gastrointestinal endoscopy, followed by anesthesia during the surgical/procedure of
nontracheal intubation, induction and maintenance of general anesthesia, and sedation
during intensive care by China in 2020.
manufactured by Haisco Pharmaceutical Group Co., Ltd. (Chengdu, China), then
commercialized in China now, which is still an investigational drug in United States as of
drafting time. Ciprofol (1), a novel propofol (2) analog, is emerging as a captivating
alternative in future, drawing increasing interest within the medical community with less
dose and less injection pain and better cardiovascular stability.
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.
isoflurane/sevoflurane/desflurane) that are volatile, and the later one including
thiopental was banned), benzodiazepines (midazolam and
Based in China National Medical Products Administration, ciprofol (1, SiShuning,
1
the former one including nitrous oxide, halothane and
2
Ciprofol (1) is independently developed and
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Chemistry and Pharmacology of Drug Discovery
1. Background
Undoubtedly, propofol (2) does build up the start of a new era in anesthesiology and expire
the patent, which is widely used in clinics. Propofol (2), marketed as Diprivan, also known
as 2,6-diisopropylphenol, is the most popular drug for anesthesia since approved by FDA
in 1989. It appears to be an ideally rapidly acting short-acting agent that results in a
decreased level of consciousness and a lack of memory for events, while pain on injection,
lipid accumulation and bacterial contamination still bring some concerns.
3
propofol (2) causes excitation.
Since its discovery in 1973,4 propofol (2) was meticulously
developed in the United Kingdom by Imperial Chemical Industries under the designation
5
ICI 35868, patented by John Glen and Roger James.
Interestingly, the initial propofol (2)
formulation, a 1% preparation formulated in Cremophor EL as the vehicle, which was
introduced in 1977, faced withdrawal due to the occurrence of anaphylactic reactions
associated with the Cremophor EL. Consequently, it was reformulated as an emulsion
comprising a mixture of soybean oil and propofol (2) in water, and subsequently
relaunched in 1986
in Europe and was approved by the FDA in 1989. Current
formulations comprises 1% or 2% (w/v) propofol (2), 10% soya bean oil, 1.2% egg
phosphatide, and 2.25% glycerol. Also, 0.005% disodium edetate (EDTA) or metabisulfite
is allowed to delay bacterial and fungal growth in this formulation. Propofol (2) serves as
a reliable agent for surgical anesthesia, as well as procedural sedation and intensive care
unit (ICU) sedation over the past 30 years.
high risk of brain injury associated with anesthesia in infants.
In 2016, FDA issued a warning regarding the
6
The prolonged exposure to
anesthesia exceeding three hours, as well as the repeated use of general anesthetics and
sedative drugs in infants or women during mid-pregnancy, can have a detrimental impact
on the development of children's brains. In a rhesus monkey study, neurotoxicity was
demonstrated to be associated with the application of propofol (2).
(2) has demonstrated its success for its rapid onset of anesthesia, rapid recovery in clinical
practice, while adverse drug reactions (ADRs) including local pain, cardiovascular and
respiratory depression, and drop in blood pressure, are reported synchronously.
Similar research about this kind of phenol analogs, like PF0713 (3),8 and fospropofol
9
(4, trade name Lusedra used by Eisai Inc, one prodrug),
are developed to clinical phase
and approved, respectively.
PF0713 (3), (R,R)-2,6-di-sec-butylphenol, is a single diastereomer containing two
defined chiral carbons of the R-configuration, and improves the potency with 10-fold more
than propofol (2) (0.38 vs 4.1 µg/mL), inducing brief propofol (2)-like anesthesia without
10
pain on injection.
Fospropofol (4),10 is a water-soluble phosphate pro-drug of propofol (2), which is
converted to propofol (2) within a few minutes of i.v. injection as moderate sedation
without pain on injection. However, it was refused for more profound sedation. The most
frequently recorded adverse reaction is paresthesia (including burning, tingling, and
1
Occasionally,
7
Together, propofol
2
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Chapter 12. Ciprofol (Cipepofol)
stinging) and/or pruritus, usually manifested in the perineal region within 5 minutes after
administration. FDA requires that it should be administered only by persons trained in the
administration of general anesthesia and not involved in the conduct of the diagnostic or
therapeutic procedure.
Herein, ciprofol (1) is designed and expected to improve potency of previous propofol
(2) with lower side effects (Figure 1).
Figure 1. 2,6-Disubstituted phenol anesthesia-propofol (2) analogs
Table 1. Approved 2,6-substituted phenol for anesthesia
Deserved of mentioning, propofol (2) has been approved to treat five indications
1), followed by fospropofol (4) and ciprofol (1). Fospropofol (4) has been only
(Table
approved to one indication (Monitored anesthesia care [MAC] sedation in adult patients)
without more profound sedation so far. Subsequently, ciprofol (1) has four indications now.
According to the GABA-A receptor binding assay,
potency than propofol (2) and PF0713 (3). In a phase II clinical trial including 39 Chinese
ICU patients,
dosage less than propofol (2). Related treatment emergent adverse events (TEAEs) are
hypotension (7.7% vs 23.1%, P = 0.310) and sinus bradycardia (3.8% vs 7.7%, P = 1.000)
in the ciprofol (1) and propofol (2) groups, respectively. Ciprofol (1) is rapidly metabolized
and accumulates at the low concentrations after continuous infusion in a stable circulatory
system compared to propofol (2).
11
ciprofol (1) exhibits much higher
12
ciprofol (1) shows good tolerance and efficacy for sedation with 5 times
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Many clinical trials about the efficacy of ciprofol (1) have been carried out in
different indications in different Phase in Australia and China, mostly in head-to-head
evaluation with propofol (2) (Table 2).2 More and more clinic data shows ciprofol (1) has
a comparable efficacy and safe profile in 5 times less dosage with propofol (2), bringing
patients to lower injection pain.
Chemistry and Pharmacology of Drug Discovery
Table 2. Clinical trials of ciprofol (1)
In a phase 3, multicenter, randomized, double-blind, comparative study,19 both
ciprofol (1, 0.4 mg/kg) and propofol (2, 2.0 mg/kg) groups demonstrated anesthesia
induction success rates of 100.0%. The lower limit of the 95% confidence interval (−4.18%
difference) suggests that ciprofol (1) is non-inferior to propofol (2), substantiating its
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Chapter 12. Ciprofol (Cipepofol)
comparable effectiveness in achieving successful anesthesia induction. Furthermore, the
ciprofol (1) group exhibits a significantly lower incidence of injection pain compared to
the propofol (2) group, with rates of 6.8% and 20.5% respectively (p < 0.05). This finding
highlights the favorable profile of ciprofol (1) in terms of reduced discomfort upon
administration when compared to propofol (2). Additionally, fewer cases were observed
where the Bispectral Index (BIS) exceeded 60 within 15 minutes of intravenous
administration, suggesting that ciprofol (1) had the potential to achieve a more optimal
sedation level during the post-induction period, even under an equivalent dosage regimen
to propofol (2). This study highlights the advantages of ciprofol (1) in terms of
cardiovascular stability and maintaining the desired sedation state.
2. Pharmacology
Provided by previous research about propofol (2), ciprofol (1) shares similar mechanism
of action with propofol (2), targeting the intricate γ-aminobutyric acid (GABA) receptor
system preferentially, whose
hyperpolarization of the postsynaptic membrane
neurotransmitter,
33
which acts a key role in the balanced inhibitory/excitatory
neuronal network in the central nervous system. A series of distinct classes of drugs
(benzodiazepines and benzodiazepine-like compounds, beta-carbolines steroids,
barbiturates, alcohols, picrotoxin, tertbutylbicyclophosphorothionate (TBPS) exert
their effects by interacting with specific modulatory sites on the GABA receptor.
About mechanism of action for ciprofol (1), competitive binding assays on the α1β2γ2
subtype of γ-aminobutyric acid type A (GABAA) receptors
triggers GABA-evoked chloride currents at lower concentration, and enhances GABAinduced activation at higher concentrations.
experiments, the affinity of ciprofol (1) with GABAA receptors was 4-5 times higher than
that of propofol (2). Ciprofol (1) approximately has high affinity for the picrotoxin-binding
site or has an allosteric inhibition of TBPS/TBOB for binding to GABAA receptor, while
there is no affinity for benzodiazepine and GABA sites.
Considering unclear mechanism of action at atomic resolution, more and more
evidence is found with structural biology methods advancing. Generally, the formation of
an intermolecular hydrogen bond involving hydroxyl group of propofol (2) plays a
dominant role in its molecular recognition with receptors that lead to hypnosis. Atomically,
X-ray structure of GLIC (a homopentameric member of the pLGIC family
ligand-gated ion channels with propofol (2) clarifies that it binds at the entrance of the
cavity and is sandwiched between M1 and M3 and interacts mainly with T255 and Y254
via van der Waals contacts, in which the propofol (2) hydroxyl group could form a
hydrogen bond with Y254.
activation rapidly increases Cl− conductance and
GABA receptor. GABA is an inhibitory
demonstrated that ciprofol (1)
35
Besides, in whole-cell patch-clamp
)-pentameric
36
Mutations of GLIC (V242M and T255A I202A) lining the
34
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Chemistry and Pharmacology of Drug Discovery
binding site profoundly affect its general-anesthetic pharmacology and show a significant
mobility of propofol (2) within the cavity. However, no X-ray structure of ciprofol
(1) was
reported to disclose its atomic mechanism of action.
Yuki et al. demonstrated that
propofol (2) bound to the lovastatin site in leukocyte
function–associated antigen-1 (LFA-1) and inhibited the production of interleukin-2 via
37
LFA-1 in a dependent manner.
It is worth noting that this lovastatin site is also the binding
site for anesthetics isoflurane and sevoflurane.
In electrophysiological assays,38 propofol (2) allosterically enhanced the actions of
GABA at the GABA-A receptor. Propofol (2) significantly shifted the dose–response curve
of GABA-activated current towards the left without affecting the maximum of the GABA
response. It profoundly slows down the desensitization process of GABA-A receptors,
which plays a pivotal role during rapid and repetitive activation of inhibitory synapses (Bai
39
et al. 1999). Early neurochemical studies
demonstrated that propofol (2) markedly
enhanced [3H]-GABA binding in the rat cerebral cortex and dose-dependently inhibits the
35
binding of [
of GABAergic transmission such as GABA uptake and [
S]-TBPS. Furthermore, propofol (2) also influenced presynaptic mechanisms
3
H]-GABA uptake into purified
striatal synaptosomes was inhibited in a dose dependent and reversible manner by propofol
(2) (IC50 = 46 μM) GABA release. In 1988, Collins reported propofol (2) (20–50 μM)
increased GABA-mediated inhibitory transmission in rat olfactory cortex slices and
influenced positively both pre- and post-synaptic GABA-dependent neuronal inhibition.
Figure
According to Eckenhoff’s study,
2) demonstrated no hypnotic activity, but rather weak excitatory activity.
fluorine-substituted analogue (fropropofol, see
40
Furthermore, hydrogen bonding is an essential molecular characteristic for propofol (2)
41
protein binding sites inducing hypnosis.
Interestingly, in a rigorous three-layer ONIOM
(M06-2X/6-31 + G*:PM6: AMBER) study, fropropofol can bind to the protein with lower
42
binding affinity molecular binding via a halogen-bonding and benzene interaction.
3. Structure–Activity Relationship (SAR)
Here we describe the structure–activity relationship about ciprofol (1) mainly based in
James’s (1980),
largely affected by steric hindrance of the other five positions (R
Figure 2. Fluorine-substituted analogue
43
Trapani’s (1998)44 and Qin’s works11 (Figure 3). Their potencies will be
2-R6/R3-R5/R4
). Hydroxyl
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Chapter 12. Ciprofol (Cipepofol)
group is a key characteristic for hypnosis and the ortho substitution will modify the
hydrogen bond binding strength. Most structures are alkyl group substitution that is prone
to be hydrophobic domain.
Figure 3. Structure–activity relationships (SAR) of alkylphenols as anesthetic agents
For free OH group, F substitution shows poor hypnosis but a weak excitatory
41
activity.
to decrease in binding affinity.
Etherification or esterification of the phenolic hydroxyl group was demonstrated
44
For R2 and R6 position, secondary alkyl groups with a sum of 6–10 carbon atoms
show an optimal anesthetic activity apart from the most hindrance t-butyl group. Their
potencies increase with di-sec-alkyl > n-alkyl, sec-alkyl > di-n-alkyl, in which steric bulk
will benefit logP, while the steric bulk decreases potency with the carbon number of chain
(N ≥ 9). As for diastereoisomers, (R,R) and (R)-configured one are prone to own higher
potency than the other isomers.
For R3 and R5 position, substitutions in these two positions almost show poor
4
potencies, as well as R
position. Furthermore, methyl-substitution in R4 will cause a
delayed death, which may result from a p-quinonemethide intermediate via a different
43
metabolism mode.
in inhibiting [
Interestingly, halogens (Cl, Br, and I) or benzoyl substituents44 benefit
35
S]-TBPS binding, in which iodo-substitution45 exhibits poorer PK than
propofol (2) via intraperitoneal injection, resulting in failure of inducing anesthesia in
rodents without detected in mouse serum or brain. Also, I-substituent shows approximately
even six-fold less than that of propofol (2) by a regular intravenous injection.
In summary, previous SAR around R3, R
by two papers
4
43,44
to provide a good understanding to modification of these three positions,
, and R
5
position were mainly developed
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