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 inhibits the chymase enzyme in humans and hamsters, with IC50 values of 4 nM and 3 nM, respectively[1][2].

---

Fulacimstat (BAY 1142524) is an orally available chymase inhibitor that blocks the generation of profibrotic chymase-dependent factors such as angiotensin II, endothelin-1, and transforming growth factor-β1 in vitro with nanomolar half-maximal inhibitory concentration (IC₅₀). [2]

In hamsters, isoprenaline causes 24.4±1.8% cardiac fibrosis, which is dose-dependently decreased by enalapril (17.7±1.5% at 20 mg/kg) and Fulacimstat (16.4±1.2%, 12.4 ± 1.3%, and 10.9±1.4% at 1, 3 and 10 mg/kg, respectively). The hearts of hamsters exhibit reduced relaxation and contractility, along with an increase in end diastolic pressure, four weeks after MI. Without affecting blood pressure or heart rate, fulacimstat at 10 mg/kg significantly reduced the end diastolic pressure (13.2±1.4 mmHg) in comparison to placebo (19.3±2 mmHg). Additionally, Fulacimstat treatment improves the cardiac response to adrenergic stimulation and reduces the fibrotic area[1].

---

In hamsters, Fulacimstat (BAY 1142524) reduced isoprenaline-induced cardiac fibrosis and attenuated the deterioration of heart function after myocardial infarction (MI). In dogs with left-ventricular dysfunction (LVD) induced by intracoronary microembolization, Fulacimstat increased left-ventricular ejection fraction. These effects were observed at therapeutic exposures without affecting blood pressure or heart rate in the examined animal models. [2]

Male Syrian hamstersC
10 mg/kg
p.o.

In three Phase I clinical studies, pharmacokinetic assessments of Fulacimstat (BAY 1142524) were conducted in healthy male volunteers. Absorption: Following oral administration, the median time to peak plasma concentration (tₘₐₓ) was 0.5–0.75 hours in the liquid formulation (LSF) and 1.0–2.98 hours in the immediate-release tablet (IR). [2] Exposure and dose proportionality: Systemic exposure, measured by area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cₘₐₓ), appeared to be dose-proportional after single-dose administration (1–200 mg) and multiple-dose administration (5–50 mg twice daily). The dose-normalized AUC (AUC/D) was independent of the dose level. [2]
Elimination: Fulacimstat is eliminated from plasma after administration of LSF or IR tablets, with a terminal half-life (t½) ranging from 6.84 to 12.0 hours. Inter-individual variability ranges from 3.75 to 21.3 hours. [2]
Food Effects: High-fat, high-calorie diets have minimal effect on the AUC of 5 mg IR tablets (a decrease of 4.22%), but reduce Cₘₐₓ by 23.5% and prolong tₘₐₓ by approximately 2.01 hours. The 90% confidence interval (88.9%–103%) of the AUC ratio is within the 80%–125% bioequivalence range. [2]
Accumulation: Fulacimstat accumulates slowly after multiple administrations over 5 consecutive days. When 100 mg was taken once daily, the cumulative ratios of Cₘₐₓ (RACₘₐₓ) and AUC (RAAUC) over the dosing interval were 1.13 and 1.22, respectively; the corresponding ranges for the twice-daily dosing regimen (5-50 mg, BID) were 1.14-1.61 and 1.26-1.65, respectively. Pharmacokinetics changed linearly over time. [2] Bioavailability: On an empty stomach, the relative bioavailability of AUC of 5 mg immediate-release tablets compared with that of 5 mg oral solution (LSF) was approximately 106% (90% CI: 98.4-114), and the relative bioavailability of Cₘₐₓ was approximately 79.4%. [2]
Excretion: After a single dose, approximately 7.90% to 17.6% of the dose is excreted unchanged by the kidneys; after repeated dosing twice daily, approximately 19.5% to 23.7% of the dose is excreted unchanged by the kidneys, with significant inter-individual variability. The mean renal clearance is approximately 0.320 L/h. [2]

Fulacimstat (BAY 1142524) was safe and well-tolerated in healthy male volunteers at all treatment doses (single dose up to 200 mg, multiple doses up to 100 mg once daily or 50 mg twice daily). The incidence and severity of treatment-induced adverse events (TEAEs) were similar in the Fulacimstat and placebo groups. Headache was the most common TEAE. No drug-related serious adverse events were observed. The incidence of TEAEs was not dose-dependent. [2] Compared with placebo, Fulacimstat had no effect on systolic/diastolic blood pressure or heart rate after single or multiple doses. [2] No drug-induced changes in laboratory parameters (hematology, serum chemistry, coagulation function, urinalysis) were observed. Transient increases in some laboratory parameters were observed, but these were considered unrelated to the intake of the study drug. [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 being investigated in clinical trial NCT02452515 (a single-blind pilot study designed to investigate the safety and tolerability of the chymotrypsin inhibitor BAY1142524 in patients with clinically stable left ventricular dysfunction). Fulacimstat (BAY 1142524) is a novel oral chymotrypsin inhibitor being developed as a first-in-class treatment for left ventricular dysfunction following myocardial infarction. Its mechanism of action involves local inhibition of chymotrypsin (a serine protease secreted after tissue injury), thereby blocking the production of profibrotic factors such as angiotensin II and reducing adverse cardiac remodeling. [2] Based on human pharmacokinetic data and preclinical pharmacodynamic models, a dose of 4 mg twice daily or 20 mg once daily is expected to provide therapeutic plasma concentrations (free drug concentrations higher than human chymotrypsin IC₅₀ 4 nM) over nearly 24 hours. [2]
Since no changes in blood pressure and heart rate were observed, Fulacimstat is planned to be used in combination with standard hemodynamically active medications (e.g., ACE inhibitors, beta-blockers) in post-myocardial infarction patients. [2]
Its pharmacokinetic characteristics allow for once-daily dosing, which may improve patient adherence in long-term treatment. [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

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.13 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: ≥ 0.5 mg/mL (1.03 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 5.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

---

View More

Solubility in Formulation 3: ≥ 0.5 mg/mL (1.03 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 5.0 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.)