Sebetralstat
(Synonyms: KVD900) 目录号 : GC65958
Sebetralstat (KVD900) 是一种血浆激肽酶抑制剂 (WO2016083820)。Sebetralstat 可用于代谢疾病的研究。
Cas No.:1933514-13-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Sebetralstat (KVD900) is a plasma kallikrein inhibitor (WO2016083820). Sebetralstat can be used for the research of metabolic diseases[1].
Sebetralstat is a plasma kallikrein inhibitor[1].
| Cas No. | 1933514-13-6 | SDF | Download SDF |
| 别名 | KVD900 | ||
| 分子式 | C26H26FN5O4 | 分子量 | 491.51 |
| 溶解度 | DMSO : ≥ 125 mg/mL (254.32 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.0345 mL | 10.1727 mL | 20.3455 mL |
| 5 mM | 0.4069 mL | 2.0345 mL | 4.0691 mL |
| 10 mM | 0.2035 mL | 1.0173 mL | 2.0345 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Sebetralstat (KVD900): A Potent and Selective Small Molecule Plasma Kallikrein Inhibitor Featuring a Novel P1 Group as a Potential Oral On-Demand Treatment for Hereditary Angioedema
J Med Chem 2022 Oct 27;65(20):13629-13644.PMID:36251573DOI:10.1021/acs.jmedchem.2c00921.
Hereditary angioedema (HAE) is a rare genetic disorder in which patients experience sudden onset of swelling in various locations of the body. HAE is associated with uncontrolled plasma kallikrein (PKa) enzyme activity and generation of the potent inflammatory mediator, bradykinin, resulting in episodic attacks of angioedema. Herein, we disclose the discovery and optimization of novel small molecule PKa inhibitors. Starting from molecules containing highly basic P1 groups, which typically bind to an aspartic acid residue (Asp189) in the serine protease S1 pocket, we identified novel P1 binding groups likely to have greater potential for oral-drug-like properties. The optimization of P4 and the central core together with the particularly favorable properties of 3-fluoro-4-methoxypyridine P1 led to the development of Sebetralstat, a potent, selective, orally bioavailable PKa inhibitor in phase 3 for on-demand treatment of HAE attacks.
Absorption, metabolism, and excretion of [14C]-sebetralstat (KVD900) following a single oral dose in healthy male participants
Xenobiotica 2022 Jul;52(7):707-717.PMID:36200371DOI:10.1080/00498254.2022.2132187.
Sebetralstat is an investigational oral plasma kallikrein inhibitor for the on-demand treatment of hereditary angioedema. Six healthy male participants received one dose of 600 mg (540 µCi) [14C]-sebetralstat. Plasma concentrations of Sebetralstat and levels of total radioactivity in plasma, urine, and faeces were determined. Metabolite profiles of radioactivity were generated, and major metabolites structurally characterised.Radioactivity was rapidly absorbed and was excreted with a mean of 95.8% (63.4% faeces; 32.4% urine) recovered by 216 h. Sebetralstat was the major drug-related component in urine and faeces, although metabolism predominated overall (main metabolites: M19 (des-[methoxy-fluoro-methylpyridine]-sebetralstat), M10 (N-des-pyridone-sebetralstat-carboxylic acid), M3 (pyridine O-desmethyl-sebetralstat), and M34 (pyridine dioxy-dihydro-sebetralstat)). Sebetralstat was the main radiolabelled component in plasma (mean of 64.1% of the total radioactivity AUC0-24), followed by relatively low proportions of metabolites: M19 (7.10%), M3 (4.01%), and M10 (4.00%). Although M19 was >10% of the plasma radioactivity AUC0-24, in one participant it comprised a mean of <10% of AUC0-24. Plasma levels of M19 were measured at the NOAEL dose in a rat toxicology study, where higher exposure was observed vs. that in humans.Given these findings and the lack of pharmacological activity of M19, it was concluded that there was no unique or disproportionate circulating metabolite in humans.
An investigational oral plasma kallikrein inhibitor for on-demand treatment of hereditary angioedema: a two-part, randomised, double-blind, placebo-controlled, crossover phase 2 trial
Lancet 2023 Feb 11;401(10375):458-469.PMID:36774155DOI:10.1016/S0140-6736(22)02406-0.
Background: Guidelines recommend effective on-demand therapy for all individuals with hereditary angioedema. We aimed to assess the novel oral plasma kallikrein inhibitor, Sebetralstat, which is in development, for on-demand treatment of hereditary angioedema attacks. Methods: In this two-part phase 2 trial, individuals with type 1 or 2 hereditary angioedema aged 18 years or older were recruited from 25 sites, consisting of specialty outpatient centres, across nine countries in Europe and the USA. Individuals were eligible if they had experienced at least three hereditary angioedema attacks in the past 93 days, were not on prophylactic therapy, and had access to and the ability to self-administer conventional attack treatment. In part 1 of the trial, participants were given a single 600 mg open-label oral dose of Sebetralstat to assess safety, pharmacokinetics, and pharmacodynamics of the dose. Part 2 was a randomised, double-blind, placebo-controlled, two-sequence, two-period (2 × 2) crossover trial; participants were randomly assigned (1:1) to either sequence 1, in which they were given a single dose of 600 mg of Sebetralstat to treat the first eligible attack and a second dose of placebo to treat the second eligible attack, or sequence 2, in which they were given placebo to treat the first eligible attack and then 600 mg of Sebetralstat to treat the second eligible attack. Participants and investigators were masked to treatment assignment. The primary endpoint was time to use of conventional attack treatment within 12 h of study drug administration, which was assessed in all participants who were randomly assigned to treatment and who received study drug for two attacks during part 2 of the study. Safety was assessed in all participants who received at least one dose of study drug, starting in part 1. This study is registered with ClinicalTrials.gov, NCT04208412, and is completed. Findings: Between July 2, 2019, and Dec 8, 2020, 84 individuals were screened and 68 were enrolled in part 1 and received Sebetralstat (mean age 38·3 years [SD 13·2], 37 [54%] were female, 31 [46%] were male, 68 [100%] were White). 42 (62%) of 68 participants completed pharmacokinetic assessments. Sebetralstat was rapidly absorbed, with a geometric mean plasma concentration of 501 ng/mL at 15 min. In a subset of participants (n=6), plasma samples obtained from 15 min to 4 h after study drug administration had near-complete protection from ex vivo stimulated generation of plasma kallikrein and cleavage of high-molecular-weight kininogen. In part 2, all 68 participants were randomly assigned to sequence 1 (n=34) or sequence 2 (n=34). 53 (78%) of 68 participants treated two attacks (25 [74%] in the sequence 1 group and 28 [82%] in the sequence 2 group). Time to use of conventional treatment within 12 h of study drug administration was significantly longer with Sebetralstat versus placebo (at quartile 1: >12 h [95% CI 9·6 to >12] vs 8·0 h [3·8 to >12]; p=0·0010). There were no serious adverse events or adverse event-related discontinuations. Interpretation: Oral administration of Sebetralstat was well tolerated and led to rapid suppression of plasma kallikrein activity, resulting in increased time to use of conventional attack treatment and faster symptom relief versus placebo. Based on these results, a phase 3 trial to evaluate the efficacy and safety of two dose levels of Sebetralstat in adolescent and adult participants with hereditary angioedema has been initiated (NCT05259917). Funding: KalVista Pharmaceuticals.