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NTP42 is a novel thromboxane A2 (TXA2) receptor antagonist with an IC50 of 3.278 nM for antagonizing T prostanoid receptor (TP)- mediated [Ca2+] mobilization following stimulation of cells with the alternative TP agonist U46609. The pulmonary arterial hypertension (PAH) condition can be treated with NTP42. Treatment for pulmonary arterial hypertension (PAH) is presently being developed with NTP42. Excessive pulmonary vasoconstriction, vascular remodeling, inflammation, fibrosis, in situ thrombosis, and right ventricular hypertrophy are just a few of the pathophysiological features of PAH, a devastating disease.
| Targets |
TXA2
NTP42 targets the T prostanoid receptor (TP), specifically both the TPα and TPβ isoforms. [2] • Antagonism of TPβ‑mediated intracellular calcium mobilization stimulated by U46619 (TXA₂ mimetic): IC₅₀ = 8.86 ± 3.07 nM. [2] • Antagonism of TPβ‑mediated intracellular calcium mobilization stimulated by 8‑iso‑PGF₂α: IC₅₀ = 8.04 ± 3.74 nM. [2] • Antagonism of U46619‑induced human platelet aggregation: IC₅₀ = 10.6 ± 1.7 nM. [2] • In HEK.TPα cells, inhibition of U46619‑mediated calcium mobilization: IC₅₀ = 56.2 ± 4.84 nM (patent data). [1] • In HEK.TPβ cells, inhibition of U46619‑mediated calcium mobilization: IC₅₀ = 8.25 ± 0.73 nM (patent data). [1] • No agonist or antagonist activity at other prostanoid receptors (DP₁, EP₁, EP₂, EP₃, EP₄, FP, IP) up to 10 μM. [2] |
|---|---|
| ln Vitro |
• NTP42 potently inhibited U46619‑induced intracellular calcium mobilization in HEK cells stably overexpressing the human TPβ isoform (HEK.TPβ cells), with an IC₅₀ of 8.86 ± 3.07 nM. It also inhibited 8‑iso‑PGF₂α‑induced calcium mobilization in the same cell line with an IC₅₀ of 8.04 ± 3.74 nM. [2]
• NTP42 antagonized U46619‑induced aggregation of human platelets in ex vivo assays using platelet‑rich plasma (PRP), showing an IC₅₀ of 10.6 ± 1.7 nM. [2] • In selectivity assays, NTP42 (up to 10 μM) exhibited no agonist or antagonist effects on signaling mediated by the prostacyclin receptor (IP), prostaglandin D₂ receptor (DP₁), prostaglandin E₂ receptors (EP₁, EP₂, EP₃, EP₄), or prostaglandin F₂α receptor (FP) in respective cell lines. [2] • NTP42 did not inhibit TXA₂ synthase (TXAS), distinguishing it from dual TXAS/TP antagonists. [2] |
| ln Vivo |
NTP42 (0.25 mg/kg BID) was successful in the hemodynamic evaluation of the PAH trajectory model induced by monocrotaline (MCT) (a 28-day medication regimen initiated within 24 hours of MCT). NTP42 lowers right systolic blood pressure (RSVP) and mean pulmonary artery pressure (mPAP), two measures of PAH brought on by MCT. Moreover, NTP42 was linked to a significant reduction in pulmonary vascular proliferation, activation of inflammatory mast cells, and fibrosis in animals treated with MCT when combined with sildenafil and Selelexipag[2].
• In the monocrotaline (MCT)-induced PAH rat model, oral administration of NTP42 (0.25 mg/kg BID for 28 days) significantly reduced MCT‑induced increases in mean pulmonary arterial pressure (mPAP) from 28.5 ± 1.0 mmHg (MCT only) to 18.7 ± 0.9 mmHg (P < 0.0001). [2] • NTP42 also significantly reduced right ventricular systolic pressure (RVSP) from 44.7 ± 2.2 mmHg (MCT only) to 36.6 ± 2.5 mmHg (P = 0.0229). [2] • No significant change was observed in Fulton’s index (right ventricular hypertrophy) with NTP42 treatment. [2] • Histological and morphometric analyses showed that NTP42 significantly attenuated MCT‑induced pulmonary vascular remodelling: it improved lumen:total vessel diameter ratio (P < 0.0001), reduced medial thickness (P < 0.0001), and decreased degree of vessel occlusion (P < 0.0001) compared to MCT‑only controls. [2] • NTP42 significantly reduced MCT‑induced pulmonary mast cell density (P = 0.0002) and pulmonary fibrosis (percentage fibrotic area, P = 0.0180). These effects were superior to those of Sildenafil and Selexipag. [2] • NTP42 had no deleterious effects on mean systemic arterial pressure (mAP) or heart rate (HR) in the MCT‑PAH model. [2] |
| Enzyme Assay |
• Calcium mobilization assay in HEK.TPβ cells: HEK.TPβ cells were preloaded with Fluo‑4 fluorescent dye. Cells were then incubated with increasing concentrations of NTP42 (0.00001 – 10 μM) before stimulation with either 1 μM U46619 or 10 μM 8‑iso‑PGF₂α. Fluorescence changes (indicating intracellular calcium) were measured, and IC₅₀ values were calculated from dose‑response curves. [2]
• Platelet aggregation assay: Blood from healthy volunteers was collected into sodium citrate (3.8%) and indomethacin (10 μM). Platelet‑rich plasma (PRP) was prepared by centrifugation. PRP aliquots were pre‑incubated with NTP42 (2‑fold serial dilutions from 1 μM) for 10 min at 37°C with stirring, then stimulated with 1 μM U46619. Aggregation was monitored by changes in light transmission using a platelet aggregometer (PAP‑8E), and IC₅₀ was determined. [2] |
| Cell Assay |
• HEK.TPα and HEK.TPβ cell calcium mobilization assays: HEK293 cells stably overexpressing human TPα or TPβ isoforms were cultured, preloaded with Fluo‑4, and treated with NTP42 (0.00001 – 10 μM) prior to stimulation with 1 μM U46619. Fluorescence was measured to quantify intracellular calcium. Data were expressed as percentage of control (agonist‑induced response in vehicle‑treated cells). [1][2]
• Platelet aggregation assay: Human venous blood was collected into 3.8% sodium citrate (1:9 ratio) containing 10 μM indomethacin. PRP was obtained by centrifugation (200g for 20 min). PRP (300 μl) was pre‑incubated with NTP42 (serial dilutions from 0.25 μM to 125 nM) for 10 min at 37°C with stirring. Platelet aggregation was induced by 1 μM U46619 and measured by light transmission using a PAP‑8E aggregometer. Percentage aggregation was calculated relative to control. [1][2] • Selectivity assays: Similar calcium mobilization or impedance assays were performed using cells expressing other prostanoid receptors (DP₁, EP₁, EP₂, EP₃, EP₄, FP, IP) with their respective agonists (e.g., cicaprost for IP, PGE₂ for EP receptors). NTP42 was tested at 10 μM for agonist or antagonist activity. [2] |
| Animal Protocol |
Male Wistar-Kyoto rats
0.25 mg/kg BID 28-day drug treatment was initiated within 24 h post-MCT (60 mg/kg) • MCT‑induced PAH rat model: Male Wistar‑Kyoto rats (8‑9 weeks old, 200‑250 g) received a single subcutaneous injection of monocrotaline (MCT; 60 mg/kg in DMSO) on Day 0. Control animals received DMSO vehicle. Starting on Day 1 (within 24 h post‑MCT), animals were treated twice daily (BID) by oral gavage with NTP42 (0.25 mg/kg BID) suspended in 0.375% DMSO vehicle, for 28 consecutive days. Reference groups received Sildenafil (50 mg/kg BID, PO) or Selexipag (1 mg/kg BID, PO), while negative controls received vehicle only. [2] • Haemodynamic evaluations: On Day 28, animals were anaesthetised with isoflurane (2‑2.5% in 95% O₂/5% CO₂), tracheotomised and ventilated. A cannula was inserted into the left femoral artery to measure systemic arterial pressure. After sternotomy, a catheter was introduced into the right ventricle (RV) and advanced into the pulmonary artery. Pressures (diastolic, systolic, mean) were recorded continuously using a pressure transducer and Clampfit software. Right ventricular systolic pressure (RVSP), mean pulmonary arterial pressure (mPAP), mean systemic arterial pressure (mAP) and heart rate (HR) were measured. [2] • Tissue collection and analysis: After haemodynamic measurements, animals were euthanised by exsanguination. Heart and lungs were removed en bloc. The right ventricle (RV) was dissected and weighed, and the left ventricle plus septum (LV+S) was weighed to calculate Fulton’s index (RV/(LV+S)). Left lung lobes were fixed in formalin, embedded in paraffin (FFPE), sectioned (4 μm), and stained with haematoxylin & eosin (H&E), toluidine blue (for mast cells), or Masson’s trichrome (for collagen/fibrosis). Morphometric analysis of pulmonary arterioles (≥15 μm diameter) was performed using QuPath software to measure lumen diameter, total vessel diameter, medial thickness, and degree of vessel occlusion. [2] |
| References | |
| Additional Infomation |
NTP42 is a selective TP antagonist (no agonist activity) that blocks both TXA₂ and 8‑iso‑PGF₂α signalling. It does not inhibit TXA₂ synthase, thus avoiding the unwanted rise in prostacyclin levels that caused leg pain in clinical trials with dual inhibitors like terbogrel. NTP42 is being developed for the treatment of pulmonary arterial hypertension (PAH) and shows potential to address multiple hallmarks of the disease including vasoconstriction, vascular remodelling, inflammation, fibrosis and thrombosis. Its chemical name is 1‑tert‑Butyl‑3‑[5‑cyano‑2‑[3‑[4‑(difluoromethoxy)phenyl]phenoxy]phenyl]sulfonyl‑urea (formula IV in patent). [1][2]
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| Molecular Formula |
C25H23F2N3O5S
|
|---|---|
| Molecular Weight |
515.529031991959
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| Exact Mass |
515.13
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| Elemental Analysis |
C, 58.25 H, 4.50 F, 7.37 N, 8.15 O, 15.52 S, 6.22
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| CAS # |
2055599-51-2
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| PubChem CID |
124147085
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| Appearance |
White to off-white solid powder
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| LogP |
5.3
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
36
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| Complexity |
888
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
RIIKDGPBTPECSW-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H23F2N3O5S/c1-25(2,3)29-24(31)30-36(32,33)22-13-16(15-28)7-12-21(22)34-20-6-4-5-18(14-20)17-8-10-19(11-9-17)35-23(26)27/h4-14,23H,1-3H3,(H2,29,30,31)
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| Chemical Name |
1-tert-butyl-3-[5-cyano-2-[3-[4-(difluoromethoxy)phenyl]phenoxy]phenyl]sulfonylurea
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| Synonyms |
NTP-42; NTP 42; NTP42
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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: ~31.3 mg/mL (~60.6 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.03 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 20.8 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: ≥ 2.08 mg/mL (4.03 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 20.8 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 | 1.9398 mL | 9.6988 mL | 19.3975 mL | |
| 5 mM | 0.3880 mL | 1.9398 mL | 3.8795 mL | |
| 10 mM | 0.1940 mL | 0.9699 mL | 1.9398 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT06092788 | Recruiting | Drug: NTP42:KVA4 Capsule Drug: NTP42:KVA4 Liquid |
Healthy | ATXA Therapeutics Limited | November 2023 | Phase 1 |
| NCT04919863 | Completed | Drug: NTP42:KVA4 Drug: Placebo |
Healthy | ATXA Therapeutics Limited | May 24, 2021 | Phase 1 |
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