From propofol to cipepofol (Cypsedo®), a new intravenous general anesthetic approved for adults undergoing surgery

Abstract

Propofol (1) remains the gold standard intravenous general anesthetic despite such drawbacks as injection pain, respiratory depression, and cardiovascular instability. The newly FDA-approved cipepofol (Cypsedo^®, 2) is a chiral analog incorporating a cyclopropyl ring to enhance stereospecifc binding to GABA_A receptors. Due to its four- to five-fold greater potency, cipepofol achieves anesthetic efficacy at lower induction doses (0.4–0.5 mg/kg). It retains favorable pharmacokinetic properties of propofol, including rapid onset and short duration of action, while requiring a lower lipid load in its formulation. Clinical studies have demonstrated reduced post-induction hypotension, markedly less injection pain, and improved hemodynamic stability, making it an attractive alternative for patients at increased cardiovascular or respiratory risk.

For decades, propofol (2,6-diisopropylphenol, 1) has been the cornerstone intravenous anesthetic for the induction and maintenance of general anesthesia as well as procedural sedation. It has been on the World Health Organization’s List of Essential Medicines since 2007. Its popularity stems from its rapid onset of action, predictable recovery profile, and favorable pharmacokinetic characteristics. Nevertheless, propofol is associated with several clinically significant limitations, including pain during injection, respiratory depression, and dose-dependent cardiovascular instability.

On May 29, 2026, US FDA approved cipepofol (Cypsedo^®, 2, formerly known as ciprofol or HSK3486) for the induction of general anesthesia in adults undergoing surgery. As a close structural analog of propofol, cipepofol has emerged as a potent and potentially safer alternative with improved tolerability. The compound was first patented in 2014 and subsequently described in 2017 by scientists at Haisco Pharmaceutical Co., Ltd., Sichuan, China [1, 2]. Most of the clinical studies reported to date have been conducted in Australia and China [2, 3]. Table 1 summarizes the major physicochemical, pharmacological, and clinical characteristics of cipepofol compared with propofol.

Table 1.

Comparison of cipepofol and propofol

	Propofol	Cipepofol
Structure
Chemical name	2,6-Diisopropylphenol	(R)-2-(1-Cyclopropylethyl)-6-isopropylphenol
Formula / FW	C12H18O / 178.28	C14H20O / 204.31
Stereochemistry	Achiral	Chiral ((1R) enantiomer)
cLogP	3.929	4.373
Indications	Induction and maintenance of general anesthesia; sedation in ICU	Induction of general anesthesia in adults undergoing surgery
Mechanism of action	GABAA receptor modulator: produces CNS depression via GABAA-mediated inhibition of synaptic transmission and inhibition of glutamate release	GABAA receptor modulator: produces CNS depression via GABAA-mediated inhibition of synaptic transmission and inhibition of glutamate release
Formulation	Lipid emulsion	Lipid emulsion
Induction dose	1.5 to 2.5 mg/kg	0.4 to 0.5 mg/kg
Relative potency	1	4–5✕
Onset of action	15-30 s	30-60 s
Duration of action	5-10 min	5-10 min
Side effects	• Pronounced hemodynamic drop (frequent vasodilation and hypotension)	• Mild hemodynamic drop (improved stability, significantly less post-induction hypotension)
	• High risk of apnea/respiratory depression	• Lower incidence of severe respiratory depression or hypoxemia
	• Pain on injection – very common (up to ~70% without lidocaine)	• Pain on injection – rare (typically < 10% in clinical cohorts)
FDA approval	October 2, 1989	May 29, 2026 (China, December 10, 2020)

Chemistry: the power of the cyclopropyl group

At the molecular level, the principal structural distinction between propofol and cipepofol is the replacement of one methyl group within an isopropyl substituent by a cyclopropyl group. This seemingly modest modification introduces a stereogenic center, generating two optical isomers. Pharmacological studies demonstrated that the (R)-enantiomer possesses superior affinity for GABA_A receptors and was therefore selected for clinical development [2].

Mechanism of action and increased potency of cipepofol

Like propofol, cipepofol belongs to the class of 2,6-disubstituted alkylphenols and exerts its anesthetic effects primarily through potentiation of GABA_A receptor–mediated inhibitory neurotransmission and suppression of glutamate release, producing central nervous system (CNS) depression. Introduction of the cyclopropyl group increases steric bulk and creates a chiral center, resulting in two distinct stereoisomers. The spatial arrangement of the (R)-enantiomer provides an optimal fit within the receptor binding site, leading to enhanced receptor affinity and selectivity [2, 4]. This structural refinement significantly improves anesthetic potency relative to propofol.

As a consequence of its enhanced receptor affinity, cipepofol exhibits important differences in potency, formulation requirements, and clinical dosing. Cipepofol is approximately four to five times more potent than propofol. Whereas a typical induction dose of propofol ranges from 1.5 to 2.5 mg/kg, comparable anesthetic effects can be achieved with only 0.4 to 0.5 mg/kg of cipepofol [5]. Because both drugs have poor aqueous solubility, they are formulated as lipid emulsions. The standard formulation contains 10% soybean oil for propofol and only 5% soybean oil for cipepofol. In addition, the higher potency of cipepofol allows administration of a smaller injection volume to achieve equivalent anesthetic effects. Collectively, the reduced lipid concentration and lower administered volume decrease the overall lipid burden, thereby minimizing lipid-mediated vascular irritation.

Elimination and metabolism

Like propofol, cipepofol is rapidly distributed to the CNS and undergoes efficient clearance, producing a rapid onset of action (30–60 s) and a short duration of effect (5–10 min) [4, 6]. Cipepofol is extensively metabolized in the liver, primarily through glucuronidation mediated by UGT1A9 and hydroxylation catalyzed predominantly by CYP2B6. Following intravenous administration, approximately 85% of the dose is recovered in urine, largely as inactive metabolites. The major metabolite is cipepofol glucuronide (M4, 3), accounting for approximately 51.6% of the administered dose. Hydroxylation produces metabolite 4, which subsequently undergoes glucuronidation to form M5-1 (5), accounting for approximately 19.3% of the dose (Scheme 1) [7, 8]. It has a short elimination half-life (2 to 4 h) and shows no significant drug accumulation even during prolonged continuous infusions.

Scheme 1.

Major metabolic pathways of cipepofol in humans

Indications and side effects

Cipepofol is currently approved by the FDA for the induction of general anesthesia in adults undergoing surgery. Despite this approval, propofol is expected to remain the most widely used intravenous anesthetic because of its long clinical history, extensive practitioner familiarity, and availability as a low-cost generic medication.

Nevertheless, cipepofol may offer meaningful clinical advantages in selected patient populations. During rapid-sequence induction and endotracheal intubation, cipepofol provides intubating conditions comparable to those achieved with propofol while maintaining superior cardiovascular stability. Clinical studies have shown that the incidence of post-induction hypotension decreases from more than 40% with propofol to approximately 15% with cipepofol [3, 9].

Pain on injection is among the most common adverse effects associated with propofol, occurring in up to 50–70% of patients. This effect is thought to result from activation of nociceptors in the vascular wall by the lipid emulsion required for formulation of the poorly water-soluble drug. Because cipepofol is substantially more potent and requires lower doses and smaller injection volumes, the incidence of injection pain is greatly reduced, often to single-digit percentages in clinical studies [10].

Propofol-induced systemic vasodilation and myocardial depression can be problematic in patients with compromised cardiovascular function. Clinical trials have demonstrated that cipepofol produces a smaller reduction in mean arterial pressure and decreases the need for rescue vasopressor therapy in patients with severe aortic stenosis and other cardiovascular conditions. These findings suggest a potentially improved safety profile in hemodynamically fragile patients [9].

For diagnostic and therapeutic procedures such as gastroscopy, colonoscopy, and bronchoscopy, cipepofol provides effective deep sedation. Although recovery may be approximately 1–1.5 min longer than with propofol, patients experience fewer respiratory complications, hypoxemic episodes, and choking sensations during procedures [11, 12].

As with other intravenous anesthetics, cipepofol is not devoid of adverse effects. Reported side effects include allergic reactions, bradycardia, hypotension, and respiratory depression. Continued post-marketing surveillance and broader clinical experience will further clarify its long-term safety profile.

Conclusion

Cipepofol represents a rational structural optimization of the 2,6-disubstituted alkylphenol anesthetic class. Replacement of one isopropyl substituent of propofol with a chiral cyclopropylethyl group enhances GABA_A receptor affinity and substantially increases anesthetic potency while preserving the rapid onset and short duration of action characteristic of propofol. Clinical evidence indicates that cipepofol is associated with less injection pain, greater hemodynamic stability, and a lower incidence of significant respiratory adverse events. Although the widespread use of inexpensive generic propofol is likely to continue, cipepofol offers a valuable alternative for patients in whom cardiovascular stability, respiratory safety, or procedural tolerability are of particular importance.

Declarations

Conflict of interest

The author declares no competing interests.