Sebertralstat

Boiling point: 762.3±60.0℃

Storage temp: -20℃

Solubility: DMSO: ≥125 mg/mL (254.32 mM)

Form: Solid

Color: White to Off-white

Cell Experiment

DMSO: ≥ 125 mg/mL (254.32 mM; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)

"≥" means soluble, but saturation unknown.

Preparing Stock Solutions：

Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.

Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

Sebetralstat exhibits concentration-dependent inhibition of plasma kallikrein, achieving greater than 90% mean inhibition of enzyme activity from 30 minutes through approximately 6 hours following a single 600 mg oral dose in healthy subjects. As a competitive, reversible plasma kallikrein inhibitor, sebetralstat prevents cleavage of high molecular weight kininogen, thereby reducing bradykinin production responsible for angioedema symptoms. The drug also inhibits the positive feedback mechanism of the kallikrein-kinin system, reducing factor XIIa and additional plasma kallikrein generation. Cardiac electrophysiology studies demonstrated a concentration-dependent QTc interval prolongation, with the largest mean increase of 10.4 milliseconds (upper confidence interval 15.3 milliseconds) observed at 2.5 times the maximum recommended dose. The most common adverse reaction was headache, reported in 3.2% of patients receiving 600 mg versus 1.2% with placebo. The drug's pharmacodynamic effects support its use as an on-demand treatment for acute hereditary angioedema attacks, with rapid onset and sustained enzyme inhibition throughout the typical duration of an attack.

Hereditary angioedema (HAE) is a rare genetic disease resulting in deficiency or dysfunction of C1 esterase inhibitor (C1INH) protein, leading to uncontrolled activation of the kallikrein-kinin system and episodic tissue swelling that can be life-threatening when affecting the airway. Sebetralstat is a competitive, reversible inhibitor of plasma kallikrein, a serine protease central to the pathophysiology of HAE attacks. Under normal conditions, C1INH regulates plasma kallikrein activity; however, in HAE patients with deficient or dysfunctional C1INH, uncontrolled plasma kallikrein cleaves high molecular weight kininogen (HK), releasing bradykinin, which increases vascular permeability through activation of bradykinin receptors, causing the characteristic angioedema. By competitively inhibiting plasma kallikrein, sebetralstat prevents the cleavage of HK, thereby reducing bradykinin production and treating the clinical symptoms of acute HAE attacks. Additionally, sebetralstat inhibits the positive feedback mechanism of the kallikrein-kinin system, whereby plasma kallikrein activates factor XII to factor XIIa, which in turn generates additional plasma kallikrein from prekallikrein, thus amplifying bradykinin production. This dual mechanism—direct inhibition of bradykinin generation and interruption of the amplification loop—enables sebetralstat to effectively control acute HAE attacks. The drug's oral bioavailability represents a significant advancement over previous parenteral treatments, as it allows patients to self-administer treatment at the earliest sign of an attack, aligning with treatment guidelines that recommend early intervention to prevent attack progression.