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Purity: ≥98%
BMS-986120 (BMS986120) is a novel, potent and orally bioactive antagonist of protease-activated receptor-4 (PAR4) with the potential to be used for thrombus propagation and pathological vascular occlusion. It inhibits PAR4 with IC50s of 9.5, 2.1 nM in human and monkey blood, respectively. BMS-986120 has finished a clinical trial in phase I. Human platelet thrombin receptor number is PAR4. BMS-986120's antithrombotic potential was investigated in cynomolgus monkey models of electrically-mediated carotid artery thrombosis and bleeding time (BT), as these monkeys have human-like platelet thrombin receptors. In primates, BMS-986120, either by itself or in conjunction with ASA, prevents occlusive carotid artery thrombosis with minimal effect on BT, indicating a broader therapeutic window than aspirin and clopidogrel, the antiplatelet medications of choice.
| Targets |
PAR4 (Protease-Activated Receptor 4)
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|---|---|
| ln Vitro |
BMS-986120 (BMS) comparably inhibits PA induced by PAR4-AP in vitro in both human and monkey blood (IC50 of 9.5±2.7 and 2.1±0.4 nM, respectively).
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| ln Vivo |
BMS-986120 causes simultaneous rightward shifts in the log PA dose response to PAR4-AP in monkeys, but it has no effect on the maximum response; this suggests that antagonism can be overcome. Selectivity is supported by the fact that BMS (1 mg/kg) does not inhibit PA brought on by collagen, ADP, and PAR1-AP. TW is lowered by 35±5, 49±4, and 83±4%, respectively, by BMS (0.2, 0.5, and 1 mg/kg). The maximum increases in KBT and MBT are only 2.2 and 1.8 times, respectively. A maximum antiplatelet dose of 4 mg/kg/h (n = 8) results in a slight reduction of TW by 12±2%, while KBT and MBT increase by 2.2 and 2.7 fold, respectively. Combined use of ASA and BMS (0.5 or 1 mg/kg) results in TW reductions of 54±3 and 95±2%, increases in KBT of 3.1 and 3.6 times, and increases in MBT of 2.6 and 3.3 times, for each group (n = 8). In studies involving companion monkeys, clopidogrel (0.3 mg/kg/day, n=6) by itself decreases TW by 49±6%, but it increases MBT and KBT by 8.1 and 7.3 times, respectively[1].
BMS comparably inhibited PA induced by PAR4-AP in human and monkey blood in vitro (IC50of 9.5±2.7 and 2.1±0.4 nM, respectively). In monkeys, BMS produced parallel rightward shifts in the log PA dose response to PAR4-AP without affecting maximum response, suggesting surmountable antagonism. BMS (1 mg/kg) did not inhibit PA induced by PAR1-AP, ADP and collagen, supporting selectivity. BMS (0.2, 0.5, 1 mg/kg) reduced TW by 35±5, 49±4, and 83±4%, respectively. Maximum KBT and MBT increases were only 2.2-fold and 1.8-fold, respectively. A maximum antiplatelet dose of ASA (4 mg/kg/h, n=8) slightly reduced TW by 12±2% and increased KBT and MBT by 2.2- and 2.7-fold, respectively. Co-administration of ASA and BMS (0.5 or 1 mg/kg) reduced TW by 54±3 and 95±2%, increased KBT by 3.1- and 3.6-fold, and increased MBT by 2.6- and 3.3-fold, respectively (n=8/group). In companion monkey studies, clopidogrel (0.3 mg/kg/day, n=6) alone reduced TW by 49±6%, but increased KBT and MBT by 7.3- and 8.1-fold, respectively. Conclusion: In monkeys, BMS alone or combined with ASA prevents occlusive carotid artery thrombosis with limited impact on BT, demonstrating a wider therapeutic window than the standard of care antiplatelet drugs, aspirin and clopidogrel.[1] In a cynomolgus monkey arterial thrombosis model, BMS-986120 demonstrated potent and highly efficacious antithrombotic activity. BMS-986120 also exhibited a low bleeding liability and a markedly wider therapeutic window compared to the standard antiplatelet agent clopidogrel tested in the same nonhuman primate model. These preclinical findings define the biological role of PAR4 in mediating platelet aggregation. In addition, they indicate that targeting PAR4 is an attractive antiplatelet strategy with the potential to treat patients at a high risk of atherothrombosis with superior safety compared with the current standard of care. [3] Forty healthy volunteers completed a phase 1 parallel-group PROBE trial (Prospective Randomized Open-Label Blinded End Point). Ex vivo platelet activation, platelet aggregation, and thrombus formation were measured at 0, 2, and 24 hours after (1) oral BMS-986120 (60 mg) or (2) oral aspirin (600 mg) followed at 18 hours with oral aspirin (600 mg) and oral clopidogrel (600 mg). BMS-986120 demonstrated highly selective and reversible inhibition of PAR4 agonist peptide (100 μM)-stimulated P-selectin expression, platelet-monocyte aggregates, and platelet aggregation (P<0.001 for all). Compared with pretreatment, total thrombus area (μm2/mm) at high shear was reduced by 29.2% (95% confidence interval, 18.3%-38.7%; P<0.001) at 2 hours and by 21.4% (9.3%-32.0%; P=0.002) at 24 hours. Reductions in thrombus formation were driven by a decrease in platelet-rich thrombus deposition: 34.8% (19.3%-47.3%; P<0.001) at 2 hours and 23.3% (5.1%-38.0%; P=0.016) at 24 hours. In contrast to aspirin alone, or in combination with clopidogrel, BMS-986120 had no effect on thrombus formation at low shear (P=nonsignificant). BMS-986120 administration was not associated with an increase in coagulation times or serious adverse events. Conclusions: BMS-986120 is a highly selective and reversible oral PAR4 antagonist that substantially reduces platelet-rich thrombus formation under conditions of high shear stress. Our results suggest PAR4 antagonism has major potential as a therapeutic antiplatelet strategy. [2] |
| Cell Assay |
Effect of BMS-986120 on Platelet Activation and Aggregation [2]
BMS-986120 demonstrated strong and reversible inhibition of PAR4 agonist peptide (AP; 100 μM)-stimulated platelet activation and aggregation (P<0.001 for all). Compared with pretreatment, PAR4 AP-stimulated increases in platelet P-selectin expression (%), platelet-monocyte aggregates (%), and platelet aggregation (%) were reduced by 91.7% (95% confidence interval [CI], 81.0–102.4), 80.6% (95% CI, 68.6%–92.6%), and 85.0% (95% CI, 82.0–88.1) at 2 hours and by 53.9% (95% CI, 43.2%–64.7%), 41.1% (95% CI, 28.9%–53.2%), and 6.0% (95% CI, 2.9%–9.0%) at 24 hours (P<0.001 for all; Figure 2). Plasma concentrations of BMS-986120 correlated with P-selectin expression (ρ=−0.87), platelet-monocyte aggregates (ρ=−0.88), and platelet aggregation (ρ=−0.82; P<0.001 for all; Figure III in the online-only Data Supplement). There was no effect on PAR1 AP, ADP, or arachidonic acid platelet responses (P=nonsignificant [ns] for all; Figure 2). Effect of BMS-986120 on Ex Vivo Thrombus Formation [2] BMS-986120 reduced total thrombus formation at high shear (P<0.001) but not at low shear (P=ns; Figure 3). Compared with pretreatment, total thrombus area (μm2/mm) at high shear was reduced by 29.2% (95% CI, 18.3%–38.7%; P<0.001) at 2 hours and by 21.4% (95% CI, 9.3%–32.0%; P=0.002) at 24 hours. Plasma concentrations of BMS-986120 correlated with total thrombus formation at high shear (ρ=−0.47; P<0.001) but not at low shear (ρ=−0.18; P=ns; Figure III in the online-only Data Supplement). |
| Animal Protocol |
Individual anesthetized monkeys were given orally of BMS (0.2, 0.5,1 mg/kg) or vehicle (n=8/group) 2 hour before a combination of thrombosis, BT and ex vivo biomarker experiments. Aspirin alone (ASA, 4 mg/kg/h IV) or in combination with BMS (0.5, 1 mg/kg) was also studied (n=8/group). Thrombus weight (TW) reduction, BT increase over vehicle in kidney (KBT) and mesenteric artery (MBT), and platelet aggregation (PA) inhibition were determined. Peak PA responses to activation peptides selective for PAR4 (PAR4-AP, 12.5 μM) and PAR1 (PAR1-AP, 18 μM), ADP (20 μM), and collagen (5 μg/ml) were determined by whole blood aggregometry.[1]
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| ADME/Pharmacokinetics |
Pharmacokinetic Profile of Oral BMS-986120 [2]
BMS-986120 was rapidly absorbed with peak plasma concentrations occurring at 2 hours (255±136 ng/mL; Figure 1). Plasma concentrations of BMS-986120 were halved by 4 hours (133±100 ng/mL) and <10% of the peak concentration by 24 hours (21±9 ng/mL). |
| References |
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| Additional Infomation |
In conclusion, we have demonstrated that PAR4 antagonism with BMS-986120—a highly selective and reversible oral PAR4 antagonist—substantially reduces ex vivo thrombus formation in healthy volunteers under conditions of high shear stress. BMS-986120 was well tolerated with no change in coagulation assays or serious adverse events. Given the potential hemostatic sparing effects of PAR4 antagonism, our results suggest that BMS-986120 has major potential as a novel antiplatelet agent and that further investigation in clinical trials is warranted. [2]
BMS-986120 (BMS) is a novel orally-active antagonist of protease-activated receptor-4 (PAR4), a human platelet thrombin receptor, and is in phase I clinical trial. The antithrombotic potential of BMS was studied in models of electrically-mediated carotid artery thrombosis and bleeding time (BT) in cynomolgus monkeys, which have platelet thrombin receptors similar to human.[1] Antiplatelet agents are proven efficacious treatments for cardiovascular and cerebrovascular diseases. However, the existing drugs are compromised by unwanted and sometimes life-threatening bleeding that limits drug usage or dosage. There is a substantial unmet medical need for an antiplatelet drug with strong efficacy and low bleeding risk. Thrombin is a potent platelet agonist that directly induces platelet activation via the G protein (heterotrimeric guanine nucleotide-binding protein)-coupled protease-activated receptors PAR1 and PAR4. A PAR1 antagonist is approved for clinical use, but its use is limited by a substantial bleeding risk. Conversely, the potential of PAR4 as an antiplatelet target has not been well characterized. Using anti-PAR4 antibodies, we demonstrated a low bleeding risk and an effective antithrombotic profile with PAR4 inhibition in guinea pigs. Subsequently, high-throughput screening and an extensive medicinal chemistry effort resulted in the discovery of BMS-986120, an orally active, selective, and reversible PAR4 antagonist. In a cynomolgus monkey arterial thrombosis model, BMS-986120 demonstrated potent and highly efficacious antithrombotic activity. BMS-986120 also exhibited a low bleeding liability and a markedly wider therapeutic window compared to the standard antiplatelet agent clopidogrel tested in the same nonhuman primate model. These preclinical findings define the biological role of PAR4 in mediating platelet aggregation. In addition, they indicate that targeting PAR4 is an attractive antiplatelet strategy with the potential to treat patients at a high risk of atherothrombosis with superior safety compared with the current standard of care.[3] |
| Molecular Formula |
C23H23N5O5S2
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|---|---|
| Molecular Weight |
513.589222192764
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| Exact Mass |
513.11
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| Elemental Analysis |
C, 53.79; H, 4.51; N, 13.64; O, 15.58; S, 12.48
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| CAS # |
1478712-37-6
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| PubChem CID |
72190270
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| Appearance |
White to off-white solid powder
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| LogP |
4.2
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
35
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| Complexity |
724
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
MINMDCMSHDBHKG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H23N5O5S2/c1-13-17(25-21(34-13)27-4-6-31-7-5-27)12-32-18-8-14(29-2)9-19-15(18)10-20(33-19)16-11-28-22(24-16)35-23(26-28)30-3/h8-11H,4-7,12H2,1-3H3
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| Chemical Name |
4-[4-[[6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-1-benzofuran-4-yl]oxymethyl]-5-methyl-1,3-thiazol-2-yl]morpholine
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| Synonyms |
BMS 986120; BMS-986120; 1478712-37-6; WDT28B7071; 4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-yl)morpholine; 4-[4-[[6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-1-benzofuran-4-yl]oxymethyl]-5-methyl-1,3-thiazol-2-yl]morpholine; BMS986120; compound 43 [PMID: 35729784]; 2-methoxy-6-[6-methoxy-4-[[5-methyl-2-(4-morpholinyl)-4-thiazolyl]methoxy]-2-benzofuranyl]-imidazo[2,1-b]-1,3,4-thiadiazole;
BMS986120.
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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: ~3.3 mg/mL (~6.5 mM)
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9471 mL | 9.7354 mL | 19.4708 mL | |
| 5 mM | 0.3894 mL | 1.9471 mL | 3.8942 mL | |
| 10 mM | 0.1947 mL | 0.9735 mL | 1.9471 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 |
| NCT02439190 | Completed | Drug: BMS-986120 Drug: Aspirin |
Thrombosis | Bristol-Myers Squibb | September 2015 | Phase 1 |
| NCT02208882 | Completed | Drug: BMS-986120 Drug: Placebo Drug: Midazolam |
Healthy Adult Volunteers | Bristol-Myers Squibb | August 2014 | Phase 1 |
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