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Icatibant is an artificially synthesized peptide drug with a molecular formula of C59H89N19O13S and a molecular weight accurate to 1304.54. The drug is composed of 18 amino acids, including multiple non natural amino acids such as D-arginine (D-Arg), thiazole alanine (Thi), D-tertiary leucine (D-Tic), and ornithine (Oic). Its unique amino acid arrangement endows it with special biological activity, such as introducing steric hindrance by modifying amino acids to enhance binding specificity with target receptors.
products Form
Icatibant COA
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| Certificate of Analysis | ||
| Compound name | Icatibant | |
| Grade | Pharmaceutical grade | |
| CAS No. | 130308-48-4 | |
| Quantity | 78g | |
| Packaging standard | PE bag+Al foil bag | |
| Manufacturer | Shaanxi BLOOM TECH Co., Ltd | |
| Lot No. | 202601090056 | |
| MFG | Jan 9th 2026 | |
| EXP | Jan 8th 2029 | |
| Structure |
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| Item | Enterprise standard | Analysis result |
| Appearance | White or almost white powder | Conformed |
| Water content | ≤5.0% | 0.32% |
| Loss on drying | ≤1.0% | 0.17% |
| Heavy Metals | Pb≤0.5ppm | N.D. |
| As≤0.5ppm | N.D. | |
| Hg≤0.5ppm | N.D. | |
| Cd≤0.5ppm | N.D. | |
| Purity (HPLC) | ≥99.7% | 99.8% |
| Single impurity | <0.8% | 0.54% |
| Total microbial count | ≤750cfu/g | 90 |
| E. Coli | ≤2MPN/g | N.D. |
| Salmonella | N.D. | N.D. |
| Ethanol (by GC) | ≤5000ppm | 500ppm |
| Storage | Store in a sealed, dark, and dry place below 2-8°C | |
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| C.F: | C59H89N19O13S |
| E.M: | 1304 |
| M.W: | 1305 |
| m/z: | 1304 (100.0%), 1305 (63.8%), 1306 (20.0%), 1305 (6.6%), 1306 (4.5%), 1306 (4.5%), 1307 (4.1%), 1307 (2.9%), 1306 (2.7%), 1307 (1.7%), 1307 (1.3%), 1305 (1.0%) |
| E.A: | C, 54.32; H, 6.88; N, 20.40; O, 15.94; S, 2.46 |
It is a synthetic peptide composed of 10 amino acids (molecular formula: C ₅ H ₈ N ₁ O ₁ III S, molecular weight: 1304.5), which contains 5 non natural amino acids (such as D-Tic, Hyp, Thi, etc.) in its structure, and these modifications endow it with unique biological activity. Its amino acid sequence is Arg-Pro-Pro-Hyp-Gly-Ti-Ser-D-Tic-Oic-Arg, where:
D-Tic (D-2,3-diaminopropionic acid) and Oic (octahydroindole-2-carboxylic acid) are non natural amino acids that optimize receptor binding ability through steric hindrance and charge distribution.
Hyp (hydroxyproline) and Thi (thiazole alanine) enhance their affinity for receptors through hydrogen bonding and hydrophobic interactions.
Arg (arginine) residues mimic the C-terminal structure of bradykinin and form a salt bridge with the acidic pocket of the B ₂ receptor.
Tertiary structure: It folds into a specific three-dimensional conformation through hydrophobic interactions between amino acid side chains, ionic and hydrogen bonds, making it highly complementary to the binding site of the B ₂ receptor. Its affinity (Ki=0.798 nM) is similar to that of bradykinin (Ki=0.3 nM), and it can resist degradation by bradykinin lyase. Its efficacy is 2-3 times higher than previous antagonists (such as Hoe 140).
Icatibant is a synthetic selective bradykinin B2 receptor antagonist and a peptide-based targeted therapeutic agent. It is primarily indicated for the acute attacks of hereditary angioedema (HAE), and also serves as a specific clinical drug for regulating bradykinin-mediated pathological reactions. Its mechanism of action lies in the precise blockade of the bradykinin signaling pathway, which fundamentally inhibits a series of pathological damages caused by HAE attacks.
The core pathogenesis of hereditary angioedema stems from functional deficiency or insufficient quantity of C1 esterase inhibitor in patients. As a key regulatory factor of the kallikrein-bradykinin pathway in the human body, abnormal function of this inhibitor leads to excessive activation of plasma kallikrein. The overactivated kallikrein continuously catalyzes the cleavage of high-molecular-weight kininogen to generate large amounts of active bradykinin, thereby triggering a range of typical clinical manifestations.
As a potent inflammatory and vasoactive peptide, bradykinin exerts physiological and pathological effects mainly by binding to and activating bradykinin B2 receptors on the cell membrane. Widely distributed on vascular endothelial cells, airway smooth muscle cells, gastrointestinal mucosal cells and skin tissue cells, B2 receptors act as the core targets mediating edema, pain and inflammation. Under normal physiological conditions, transient activation of B2 receptors by bradykinin participates in physiological processes such as vascular regulation and local microcirculation control. During acute HAE attacks, however, excessively accumulated bradykinin persistently and overactivates B2 receptors and initiates cascaded pathological reactions.
On one hand, B2 receptor activation widens the gaps between vascular endothelial cells and markedly increases capillary permeability. A large volume of intravascular fluid extravasates into the interstitial spaces beneath the skin and mucous membranes, resulting in localized edema that commonly occurs in the face, extremities, pharynx and gastrointestinal tract. Pharyngeal edema may cause airway obstruction and even be life-threatening. On the other hand, sustained receptor activation stimulates mild release of local inflammatory mediators, inducing tissue distending pain and burning sensation, as well as smooth muscle spasm. Patients with gastrointestinal edema may present with abdominal pain, nausea, vomiting and other discomforts.
As a competitive B2 receptor antagonist, the product shares a high structural homology with bradykinin. It can specifically bind to bradykinin B2 receptors on the cell membrane with a far higher affinity than endogenous bradykinin. Upon binding, the drug occupies receptor binding sites without activating downstream signaling cascades, thereby efficiently blocking the binding and activation of excess endogenous bradykinin to receptors and terminating the bradykinin-mediated pathological cascade at the source. The product acts specifically on B2 receptors and shows no obvious binding affinity for bradykinin B1 receptors.
Since B1 receptors are mainly induced to express after chronic inflammatory stimulation and are not involved in the progression of acute HAE attacks, the drug features excellent target selectivity and minimizes off-target effects.
After administration, the product rapidly reverses bradykinin-induced vascular hyperpermeability, halts continuous fluid exudation in tissue interstitium and arrests edema progression, while relieving smooth muscle spasm and local inflammatory pain.
Clinical studies have demonstrated that the drug can block abnormal signaling pathways within dozens of minutes after dosing, gradually resolve established edema and rapidly alleviate symptoms of acute attacks. Additionally, the product does not affect the basic function of C1 esterase inhibitor nor inhibit kallikrein activity. It only targets and blocks downstream pathological pathways without interfering with normal blood coagulation, fibrinolysis and basic microcirculation regulation in the body. With a precise and safe mechanism of action targeting the core pathological links of acute HAE attacks, the product is currently one of the primary clinical drugs for symptomatic treatment of acute HAE episodes.
Pharmacokinetics
Subcutaneous injection is the conventional clinical administration route of icatibant. This route matches the physicochemical properties of the drug, delivering stable pharmacokinetic profiles with low inter-individual variability, which meets the treatment demands for acute HAE attacks in adult patients.
The product is rapidly absorbed with extremely high bioavailability following subcutaneous injection. After a single standard dose of 30 mg, its absolute bioavailability reaches 97% with nearly no absorption loss. The peak plasma concentration is achieved approximately 30 minutes post-administration, enabling rapid pharmacological effects and satisfying the needs for emergency treatment of acute attacks.
The drug has a moderate distribution volume in vivo, with a mean steady-state volume of distribution of 29.0±8.7 L. It can sufficiently penetrate into edematous lesions such as skin and mucous membranes to maintain effective local drug concentrations.
Its plasma protein binding rate is about 44%, representing a moderate binding capacity. The abundant free drug fraction ensures stable receptor antagonism, and drug efficacy will not be compromised by saturated protein binding.
In terms of metabolism, the product is not metabolized by the hepatic cytochrome P450 enzyme system. It is mainly degraded into inactive small-molecule metabolites by endogenous proteases, which effectively avoids drug-drug interactions related to hepatic drug-metabolizing enzymes. This characteristic makes it suitable for patients with underlying comorbidities who require combined medication.
The product exhibits consistent in vivo clearance profiles, with a mean plasma clearance of 245±58 mL/min and an elimination half-life of approximately 1.4±0.4 hours. Its metabolic and elimination rates are steady, posing no risk of drug accumulation. The kidney serves as the major excretion pathway: over 90% of the drug is excreted in urine in the form of inactive metabolites, while less than 10% is eliminated via the kidneys as the parent compound.
Among special populations, elderly patients show a slight decline in drug clearance and a mild increase in drug exposure. No dosage adjustment is required for patients with mild to moderate hepatic or renal impairment, while cautious use is recommended for those with severe hepatic or renal dysfunction. Overall, the product possesses favorable pharmacokinetic stability.
Its chemical synthesis requires solid-phase peptide synthesis (SPPS) technology, with core steps including resin carrier selection, amino acid coupling, cleavage, and purification.
1. Synthetic route design: gradual extension from C-end to N-terminus
The synthesis follows the classic strategy of peptide synthesis - coupling amino acids one by one from the C-terminus (carboxyl terminus) to the N-terminus (amino terminus). The specific steps are as follows:
Resin carrier selection
The commonly used Wang resin or HMP resin contains active hydroxyl groups on its surface, which can form ester bonds with the carboxyl groups of amino acids to achieve solid-phase anchoring of polypeptide chains. For example, a certain patent uses Fmoc Arg (NO ₂) - Wang resin with a substitution degree of 0.8 mmol/g as the starting carrier, and fixes the first amino acid (Fmoc Arg (NO ₂) - OH) on the resin through esterification reaction.
Removal of Fmoc protective group
Treat the resin with a 20% piperidine/DMF solution to remove the Fmoc protecting group at the N-terminus of amino acids and expose the active amino groups. For example, during the synthesis process, it is necessary to ensure the complete removal of Fmoc groups through 10 repeated "stirring dissolution reaction" steps.
Amino acid coupling one by one
Conjugate protected amino acids in sequence, usually using HBTU/HOBt/DIPEA system as the coupling reagent. For example, in the synthesis of etibant resin, icatibant is necessary to sequentially couple Fmoc-Oic OH, Fmoc-D-Tic-OH, Fmoc-Ser (tBu) - OH, etc. After each coupling, the reaction endpoint needs to be detected using the indene ketone method to ensure that the coupling efficiency is greater than 99%.
Cracking and deprotection
After completing all amino acid conjugates, the peptide was cleaved from the resin using a mixture of trifluoroacetic acid (TFA) and lysis buffer (TFA/phenol/TIS/water=95:2.5:0.5), while removing side chain protecting groups (such as tBu, Pbf, etc.). For example, in a certain method, 130.1g of etibant Wang resin is reacted at 15 ℃ for 3 hours, and after cracking, 80.2g of crude product with a purity of 55.0% is obtained.
2. Key technology: precise introduction of non natural amino acids
The structure contains multiple non natural amino acids, and its synthesis requires solving the following technical difficulties:
Introduction of D-Tic
D-Tic (octahydroindole-2-carboxylic acid) is a rigid cyclic amino acid, and its introduction requires special coupling conditions. For example, a certain patent uses Fmoc Ser (tBu) - D-Tic-OH dipeptide fragments for coupling, significantly reducing the generation of missing peptide impurities (such as des-D-Tic-etibant).
Thi's Stereoscopic Control
Thi (thiazole alanine) contains sulfur atoms and is prone to racemization. By optimizing the coupling reagents (such as DIC/HOBt) and reaction temperature (room temperature), racemic impurities (such as D-Thi-ertiban) can be controlled below 0.03%.
Arg side chain protection
The side chain of arginine contains guanidine groups and needs to be protected with Pbf or NO ₂ groups. For example, in the synthesis process, using Boc-D-Arg (NO ₂) - OPvp as the last amino acid can reduce the generation of missing peptide impurities (such as des-D-Arg-ertiban).
3. Optimization strategy: Improve yield and purity
Dipeptide fragment strategy
Pre synthesizing dipeptide fragments (such as Fmoc Arg (NO ₂) - Pro OH, Fmoc Ser (tBu) - D-Tic-OH) from adjacent two amino acids can reduce missing peptide impurities in the coupling step. For example, a certain method reduces the total impurity content from 8.2% to 1.5% by using dipeptide fragments.
Optimization of cracking conditions
Adjusting the composition of the cracking solution (such as increasing the proportion of phenol) and reaction time can improve the purity of the crude product. For example, a certain patent uses a cracking solution with TFA/phenol/TIS/water=92.5:2.5:2.5 to increase the purity of the crude product from 55.0% to 81.7%.
Innovation in Purification Process
Purification using two-step reverse phase chromatography: the first step uses a 0.1% TFA/water acetonitrile gradient elution, and the second step uses a 0.15% ammonium acetate solution acetonitrile gradient elution, resulting in a purity greater than 99.5% of etibant. For example, a certain method increases the yield from 55.2% to 75% through two-step purification.
4. Industrial Application: Balancing Cost and Efficiency
Resin substitution and recycling
Developing low-cost resin carriers (such as polystyrene polyethylene glycol copolymers) can reduce raw material costs. For example, a certain patent uses recyclable resin, which reduces the cost of a single batch by 30%.
Continuous flow synthesis technology
Introducing microreactors or fixed bed reactors to achieve continuous production of amino acid coupling and shorten the synthesis cycle. For example, a certain enterprise has shortened the single batch synthesis time from 72 hours to 24 hours through continuous flow technology.
Green Chemical Process
Use low toxicity solvents (such as ethyl acetate instead of dichloromethane) and catalysts (such as enzyme catalyzed coupling) to reduce environmental pollution. For example, a study used lipase catalyzed coupling to reduce solvent usage by 50%.
The chemical synthesis of the product requires solid-phase peptide synthesis technology, which focuses on the precise introduction of non natural amino acids, optimization of cleavage conditions, and innovation of purification processes.
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