BMS 986120
目录号 : GC18717BMS 986120是一种专门针对蛋白酶激活受体4（PAR4）的化合物，在体外实验中，其对人和猴的血液中由PAR4选择性激活肽（PAR4-AP）诱导的血小板聚集（PA）具有相当的抑制作用（人和猴的半数抑制浓度IC50分别为9.5±2.7和2.1±0.4nM）。
Cas No.:1478712-37-6
Sample solution is provided at 25 µL, 10mM.
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BMS 986120 is a compound specifically targeting protease-activated receptor 4 (PAR4), which comparably inhibited platelet aggregation (PA) induced by activation peptides selective for PAR4 (PAR4-AP) in human and monkey blood in vitro (IC50 of 9.5±2.7 and 2.1±0.4nM, respectively)[1-2]. BMS 986120 demonstrated excellent antithrombotic efficacy and minimal bleeding time prolongation in monkey models relative to the clinically important antiplatelet agent clopidogrel and provides a potential opportunity to improve the standard of care in the treatment of arterial thrombosis[3].
In vitro, when MEG-01 cells were pretreated with 10μM BMS 986120 for 30 minutes, the reduction in circularity induced by protease-activated receptor 1 (PAR1) and PAR4 was found to be completely blocked[4]. The blood was treated with BMS 986120 at concentrations of 0.01, 0.1, and 1μM for 15, 30, and 60 minutes, and BMS 986120 inhibited PAR4‐AP‐induced platelet activation in a concentration- and time-dependent manner[5].
In vivo, BMS 986120, administered to Traumatic brain injury (TBI)-injured mice (1mg/kg, 2mg/kg; intragastrically), was found to significantly ameliorate the TBI-induced neuronal damage in mice[6]. In monkeys, administration of BMS 986120 at a dose of 0.2mg/kg via oral gavage resulted in reversible inhibition of platelet aggregation and reduction of thrombus weight, with effects returning to baseline within 24 hours after the last dose[7].
References:
[1] Holinstat M, Bray PF. Protease receptor antagonism to target blood platelet therapies. Clin Pharmacol Ther. 2016;99(1):72-81.
[2] Pancras C Wong, et al. Abstract 175: A Novel Orally-Active Small-Molecule Antagonist of the Platelet Protease-Activated Receptor-4, BMS-986120, Inhibits Arterial Thrombosis With Limited Impact on Hemostasis in Cynomolgus Monkeys. Stroke. 2018;47:A175.
[3] Priestley ES, Banville J, Deon D, et al. Discovery of Two Novel Antiplatelet Clinical Candidates (BMS-986120 and BMS-986141) That Antagonize Protease-Activated Receptor 4. J Med Chem. 2022;65(13):8843-8854.
[4] Heo Y, Jeon H, Namkung W. PAR4-Mediated PI3K/Akt and RhoA/ROCK Signaling Pathways Are Essential for Thrombin-Induced Morphological Changes in MEG-01 Cells. Int J Mol Sci. 2022;23(2):776.
[5] Berry J, Harper MT. Protease-activated receptor antagonists prevent thrombosis when dual antiplatelet therapy is insufficient in an occlusive thrombosis microfluidic model. Res Pract Thromb Haemost. 2022;6(3):e12703.
[6] Luo J, Wu X, Liu H, et al. Antagonism of Protease-Activated Receptor 4 Protects Against Traumatic Brain Injury by Suppressing Neuroinflammation via Inhibition of Tab2/NF-κB Signaling. Neurosci Bull. 2021;37(2):242-254.
[7] Wong PC, Seiffert D, Bird JE, et al. Blockade of protease-activated receptor-4 (PAR4) provides robust antithrombotic activity with low bleeding. Sci Transl Med. 2017;9(371):eaaf5294.
BMS 986120是一种专门针对蛋白酶激活受体4（PAR4）的化合物，在体外实验中，其对人和猴的血液中由PAR4选择性激活肽（PAR4-AP）诱导的血小板聚集（PA）具有相当的抑制作用（人和猴的半数抑制浓度IC50分别为9.5±2.7和2.1±0.4nM）[1-2]。与临床上重要的抗血小板药物氯吡格雷相比，BMS 986120在猴模型中展现出卓越的抗血栓形成效果，并且几乎不会延长出血时间，为改善动脉血栓治疗的标准护理提供了潜在机会[3]。
在体外，当MEG-01细胞预先用10μM的BMS 986120处理30分钟后，由蛋白酶激活受体1（PAR1）和PAR4诱导的圆形度降低被完全阻断[4]。此外，当血液用BMS 986120以0.01、0.1和1μM的浓度处理15、30和60分钟时，BMS 986120以浓度和时间依赖的方式抑制了由PAR4-AP诱导的血小板激活[5]。
在体内，BMS 986120被给予患有创伤性脑损伤（TBI）的小鼠（剂量为1mg/kg和2mg/kg，通过胃内给药），结果发现其显著改善了小鼠的TBI诱导的神经损伤[6]。在猴实验中，通过口服灌胃给予BMS 986120剂量为0.2mg/kg，可导致血小板聚集的可逆性抑制和血栓重量的减少，这些效果在最后一次给药后24小时内恢复到基线水平[7]。
| Cell experiment [1]: | |
Cell lines | MEG-01 cells |
Preparation Method | Cells were stained with calcein-AM (1μg/mL) and pretreated with 10μM of BMS 986120, and then activation peptides selective for protease-activated receptor 1 (PAR1-AP) (100μM), PAR4-AP (100μM), or thrombin (0.1U/mL) were applied for 30 min. |
Reaction Conditions | 10μM; 30min |
Applications | PAR1 and PAR4 activation significantly reduced the circularity of MEG-01 cells, and the reduction in circularity by PAR1 and PAR4 was completely blocked by pretreatment with BMS 986120, respectively. |
| Animal experiment [2]: | |
Animal models | Monkey |
Preparation Method | In the BMS 986120 study, 32 monkeys were randomly assigned in a blinded fashion to one of four groups, with eight subjects per group: (i) vehicle, (ii) BMS 986120 (0.2mg/kg), (iii) BMS 986120 (0.5mg/kg), and (iv) BMS 986120 (1mg/kg). On the day of the experiment, monkeys were dosed orally by gavage with BMS 986120 or vehicle [40:60 (w/w) d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS)/polyethylene glycol 400 (PEG-400)] at 2ml/kg. Two hours after the last oral dose, blood samples were collected for the measurement of platelet aggregation and concentration of BMS 986120. At the end of the experiment, blood samples were collected for the determination of whole-blood platelet aggregation [agonists: 20μM ADP, collagen (5μg/ml), 18μM PAR1-AP, and 1.56 to 400μM PAR4-AP], clotting times, and plasma concentration of BMS 986120. |
Dosage form | 0.2mg/kg; 2h, 4h, 24h; orally by gavage |
Applications | In blood obtained before oral administration of BMS 986120 (before treatment), all three PAR4-AP concentrations generated maximal aggregation. At 2 and 4 hours after BMS 986120 dosing, the inhibition of platelet aggregation induced by 6.25μM PAR4-AP was near complete, but the aggregation response to 25μM PAR4-AP was unaffected. Consistent with reversible binding to the receptor, the platelet aggregation responses returned to pretreatment baseline by 24 hours in all BMS 986120-treated animals, with drug concentrations dropping below 1nM. |
References: | |
| Cas No. | 1478712-37-6 | SDF | |
| 化学名 | 2-methoxy-6-[6-methoxy-4-[[5-methyl-2-(4-morpholinyl)-4-thiazolyl]methoxy]-2-benzofuranyl]-imidazo[2,1-b]-1,3,4-thiadiazole | ||
| Canonical SMILES | COC1=CC2=C(C=C(C3=CN4C(SC(OC)=N4)=N3)O2)C(OCC5=C(C)SC(N6CCOCC6)=N5)=C1 | ||
| 分子式 | C23H23N5O5S2 | 分子量 | 513.6 |
| 溶解度 | DMSO : 3.33 mg/mL (6.48 mM; ultrasonic and warming and heat to 80°C) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.947 mL | 9.7352 mL | 19.4704 mL |
| 5 mM | 0.3894 mL | 1.947 mL | 3.8941 mL |
| 10 mM | 0.1947 mL | 0.9735 mL | 1.947 mL |
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动物数量 | 只 |
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