Fulacimstat   中文名称: 伏拉西司他

human chymase enzyme (IC50 = 4 nM); hamster chymase enzyme (IC50 = 3 nM)
Fulacimstat inhibits the chymase enzyme in humans and hamsters, with IC50 values of 4 nM and 3 nM, respectively[1][2].

Fulacimstat 抑制人类和仓鼠的食糜酶，IC50 值分别为 4 nM 和 3 nM[1][2]。

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Fulacimstat (BAY 1142524) 是一种口服有效的糜酶抑制剂，在体外能以纳摩尔级的半数抑制浓度阻断糜酶依赖性促纤维化因子（如血管紧张素II、内皮素-1和转化生长因子-β1）的生成。 [2]

在仓鼠中，异丙肾上腺素导致 24.4±1.8% 的心脏纤维化，依那普利（20 mg/kg 时为 17.7±1.5%）和 Fulacimstat（20 mg/kg 时为 16.4±1.2%、12.4 ± 1.3% 和 10.9±1.4%）呈剂量依赖性降低。分别为 1、3 和 10 毫克/千克）。心肌梗死后四个星期，仓鼠的心脏表现出松弛和收缩力降低，舒张末压增加。在不影响血压或心率的情况下，与安慰剂（19.3±2 mmHg）相比，10 mg/kg fulacimstat 显着降低了舒张末压（13.2±1.4 mmHg）。此外，Fulacimstat 治疗可改善心脏对肾上腺素能刺激的反应并减少纤维化面积[1]。

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在仓鼠中，Fulacimstat (BAY 1142524) 减少了异丙肾上腺素诱导的心脏纤维化，并改善了心肌梗死后的心功能恶化。在通过冠状动脉微栓塞诱导左心室功能障碍的狗模型中，Fulacimstat 提高了左心室射血分数。在治疗性暴露剂量下，在检查的动物模型中未观察到对血压或心率的影响。 [2]

Male Syrian hamstersC
10 mg/kg
p.o.

The pharmacokinetics of Fulacimstat (BAY 1142524) were evaluated in three phase I studies in healthy male volunteers.
Absorption: Following oral administration, Fulacimstat was absorbed with a median time to peak plasma concentration (tₘₐₓ) of 0.5-0.75 hours for the liquid service formulation (LSF) and 1.0-2.98 hours for immediate-release (IR) tablets under fasting conditions. [2]
Exposure and Dose Proportionality: Systemic exposure, measured as area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cₘₐₓ), appeared to increase in proportion to the dose after single (1-200 mg) and multiple (5-50 mg twice daily) dosing. The dose-normalized AUC (AUC/D) was independent of the dose level. [2]
Elimination: Fulacimstat was eliminated from plasma with a terminal half-life (t½) ranging from 6.84 to 12.0 hours after administration of LSF or IR tablets. The interindividual range was 3.75-21.3 hours. [2]
Food Effect: A high-fat, high-calorie meal had little effect on AUC for a 5 mg IR tablet (4.22% decrease) but reduced Cₘₐₓ by 23.5% and prolonged tₘₐₓ by approximately 2.01 hours. The 90% confidence interval for the AUC ratio (88.9%-103%) was within the 80%-125% bioequivalence range. [2]
Accumulation: The accumulation of Fulacimstat was low after multiple dosing for 5 consecutive days. The accumulation ratios for Cₘₐₓ (RACₘₐₓ) and AUC over the dosing interval (RAAUC) were 1.13 and 1.22 for 100 mg once daily, and ranged from 1.14-1.61 and 1.26-1.65 for twice-daily regimens (5-50 mg BID), respectively. The pharmacokinetics were linear over time. [2]
Bioavailability: The relative bioavailability of a 5 mg IR tablet compared to a 5 mg oral solution (LSF) under fasting conditions was approximately 106% for AUC (90%CI: 98.4-114) and 79.4% for Cₘₐₓ. [2]
Excretion: Renal excretion of unchanged drug accounted for approximately 7.90% to 17.6% of the dose after single-dose administration and 19.5% to 23.7% after repeated twice-daily dosing, with high interindividual variability. The mean renal clearance was approximately 0.320 L/h. [2]

Fulacimstat (BAY 1142524) was safe and well-tolerated in healthy male volunteers at all examined doses (single doses up to 200 mg, multiple doses up to 100 mg once daily or 50 mg twice daily). The incidence and intensity of treatment-emergent adverse events (TEAEs) were similar between the Fulacimstat and placebo groups. Headache was the most common TEAE. There were no serious adverse events related to the drug. No dose relationship was observed for TEAEs. [2]
Fulacimstat had no effects on systolic/diastolic blood pressure or heart rate compared with placebo after single or repeated dosing. [2]
There was no evidence of drug-induced changes in laboratory parameters (hematology, serum chemistry, coagulation, urinalysis). Transient elevations in some laboratory values occurred but were not judged to be related to study drug intake. [2]

[1]. Abstract 13624: A Novel Chymase Inhibitor BAY 1142524 Reduces Fibrosis and Improves Cardiac Function After Myocardial Infarction in Hamster. Circulation. 2018;136:A13624.

[2]. Pharmacokinetics, Safety, and Tolerability of the Novel Chymase Inhibitor BAY 1142524 in Healthy Male Volunteers. Clin Pharmacol Drug Dev. 2018 Jun 7.

Fulacimstat is under investigation in clinical trial NCT02452515 (A Single-blind Pilot Study to Investigate Safety and Tolerability of the Chymase Inhibitor BAY1142524 in Clinically Stable Patients With Left-ventricular Dysfunction).

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Fulacimstat (BAY 1142524) is a novel, orally available chymase inhibitor being developed as a first-in-class treatment for left-ventricular dysfunction after myocardial infarction. Its mechanism of action involves local inhibition of chymase, a serine protease secreted upon tissue injury, thereby blocking the generation of profibrotic factors like angiotensin II and attenuating adverse cardiac remodeling. [2]
Based on human pharmacokinetic data and preclinical pharmacodynamic models, doses of 4 mg twice daily or 20 mg once daily are predicted to provide therapeutic plasma concentrations (unbound levels above the human chymase IC₅₀ of 4 nM) for nearly 24 hours. [2]
The absence of blood pressure and heart rate effects supports the planned combination of Fulacimstat with hemodynamically active standard-of-care medications (e.g., ACE inhibitors, β-blockers) in post-MI patients. [2]
The pharmacokinetic profile allows for once-daily dosing, which may improve patient adherence in chronic therapy. [2]

C23H16F3N3O6

487.38485622406

487.099

C, 56.68; H, 3.31; F, 11.69; N, 8.62; O, 19.70

1488354-15-9

1488354-15-9

91758792

Solid powder

1.6±0.1 g/cm3

605.8±65.0 °C at 760 mmHg

320.2±34.3 °C

0.0±1.8 mmHg at 25°C

1.650

1.97

108

1

9

3

35

984

1

FC(C1=CC=CC2=C1CC[C@H]2N1C(C(C(=O)O)=CN(C2=CC=C3C(=C2)OC(N3C)=O)C1=O)=O)(F)F

JDARDSVOVYVQST-MRXNPFEDSA-N

InChI=1S/C23H16F3N3O6/c1-27-17-7-5-11(9-18(17)35-22(27)34)28-10-14(20(31)32)19(30)29(21(28)33)16-8-6-12-13(16)3-2-4-15(12)23(24,25)26/h2-5,7,9-10,16H,6,8H2,1H3,(H,31,32)/t16-/m1/s1

1-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]pyrimidine-5-carboxylic acid

BAY1142524; BAY 1142524; BAY-1142524; Fulacimstat

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 50~97 mg/mL (102.6~199.0 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (5.13 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 0.5 mg/mL (1.03 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 5.0 mg/mL 澄清 DMSO 储备液加入 900 μL 20% SBE-β-CD 生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 0.5 mg/mL (1.03 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 5.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。