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Purity: ≥98%
Avoralstat (formerly also known as BCX-4161) is a novel, potent and orally bioavailable inhibitor of Kallikrein and Bradykinin with the potential for treatment for Hereditary angioedema. Avoralstat inhibits plasma kallikrein and suppresses bradykinin production.
| Targets |
Plasma Kallikrein (PKK) (Inhibitor, biochemical potency described as approximately 15-fold more potent than C1INH)[1]
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| ln Vitro |
C1 inhibitor (C1INH) is a master regulator of contact activation, directly suppressing PKK and blocking FXIIa's conversion of prekallikrein to plasma kallikrein (PKK). Hereditary angioedema (HAE) symptoms are partly caused by bradykinin, which is released when PKK cleaves high-molecular-weight kininogen [2].
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| ln Vivo |
In a randomized, double-blind, placebo-controlled, crossover Phase 2 clinical trial (OPuS-1), 24 patients with hereditary angioedema (HAE) type I or II received oral Avoralstat (400 mg, three times daily) or matching placebo for 28-day treatment periods, separated by a 1-week washout.[1]
Treatment with Avoralstat significantly reduced the weekly rate of adjudicated HAE attacks compared to placebo (0.82 vs. 1.27 attacks/week; adjusted difference -0.45 attacks/week, 95% CI -0.68 to -0.23, P < .001).[1] The cumulative Angioedema Activity Score over 28 days (AAS28) was lower with Avoralstat compared to placebo (64.5 vs. 97.1; adjusted difference -32.6 points, P = .007).[1] The Angioedema Quality of Life (AE-QoL) total score improved from baseline with Avoralstat treatment (-8.5 points) versus virtually no change with placebo (-0.6 points); the adjusted difference was -7.9 points (P = .004).[1] |
| Enzyme Assay |
A pharmacodynamic assay measured ex vivo plasma kallikrein (PKK) inhibition.
Plasma samples from patients were collected. In a microwell-based assay, the contact pathway was activated by adding ellagic acid to the plasma sample. The amidolytic activity of generated kallikrein was measured using a fluorogenic artificial substrate. The percentage inhibition of PKK activity was calculated by comparing activity in post-dose samples to the pre-dose baseline sample.[1] The exposure-response relationship between plasma concentrations of Avoralstat and the percent PKK inhibition was characterized using an Emax pharmacokinetic model.[1] |
| ADME/Pharmacokinetics |
Plasma samples were collected from patients on days 1, 7, 14, and 29 of the treatment period for pharmacokinetic analysis. [1] The concentration of avoralstat in plasma was measured. [1] Pharmacokinetic parameters were estimated using a non-compartmental model analysis based on data collected over 3 hours on day 14. [1]
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| Toxicity/Toxicokinetics |
Safety assessments were performed using adverse events (AEs), serious adverse events, laboratory tests, vital signs, electrocardiograms, and physical examinations. [1]
Adverse events were reported in all 24 patients. 17 patients (71%) experienced adverse events during avoratastat treatment, and 20 patients (83%) experienced adverse events during placebo treatment. [1] Adverse events that occurred in ≥2 subjects and were more frequent during avoratastat treatment included: splenomegaly (13% vs 0%), confusion (8% vs 0%), night sweats (8% vs 0%), dizziness (8% vs 0%), and dyspepsia (8% vs 4%). [1] The reporting frequencies of flatulence (42% total) and diarrhea/loose stools (33% total) were similar between the two treatment periods. [1] No patients withdrew from the study due to adverse events. One serious adverse event (angioedema attack) occurred during placebo treatment. [1] |
| References |
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| Additional Infomation |
Avoralstat has been used in studies for the prevention of HAE and hereditary angioedema. Avoralstat is an oral small-molecule plasma kallikrein (PKK) inhibitor. [1] It has been used in studies for the prevention of attacks in patients with type I and type II hereditary angioedema (HAE). [1] The study (OPuS-1) showed that 28 days of treatment with Avoralstat was generally safe and well-tolerated, and significantly reduced the incidence of HAE attacks in severely ill patients. [1] Avoralstat is considered the first oral PKK-targeting prophylaxis drug to be tested in HAE. [1]
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| Molecular Formula |
C28H27N5O5
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|---|---|
| Molecular Weight |
513.544486284256
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| Exact Mass |
513.201
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| CAS # |
918407-35-9
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| PubChem CID |
86566678
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| Appearance |
White to yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.673
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| LogP |
0.8
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
38
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| Complexity |
900
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
TUWMKPVJGGWGNL-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C28H27N5O5/c1-3-16-12-21(26(34)32-18-8-6-17(7-9-18)25(29)30)20(13-23(16)38-2)19-10-11-22(33-24(19)28(36)37)27(35)31-14-15-4-5-15/h3,6-13,15H,1,4-5,14H2,2H3,(H3,29,30)(H,31,35)(H,32,34)(H,36,37)
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| Chemical Name |
3-{2-[(4-carbamimidoylphenyl)carbamoyl]-4-ethenyl-5-methoxyphenyl}-6-[(cyclopropylmethyl)carbamoyl]pyridine-2-carboxylic acid
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| Synonyms |
BCX-4161; BCX 4161; BCX4161
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~50 mg/mL (~97.36 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.87 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.87 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9473 mL | 9.7363 mL | 19.4727 mL | |
| 5 mM | 0.3895 mL | 1.9473 mL | 3.8945 mL | |
| 10 mM | 0.1947 mL | 0.9736 mL | 1.9473 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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