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]。