Key result
Compound 6b showed improved inhibition of collagen, CRP-XL, and convulxin-mediated platelet aggregation compared to losartan, with an in vivo antithrombotic ED50 of 28.36 μmol/kg in mice.
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Compound 6b is a novel GPVI antagonist that shows promising in vitro and in vivo antithrombotic activity by inhibiting platelet aggregation.
The development of small molecule inhibitors targeting GPVI has promising therapeutic role, as they inhibit arterial thrombosis with limited risk of bleeding. Among the compounds showing in vivo antithrombotic activity, the most active compound 6b (ED 50 = 28.36 μmol/kg po in mice) showed improved inhibition for collagen (IC 50 = 6.7 μM), CRP-XL (IC 50 = 53.5 μM), and convulxin (CVX) (IC 50 = 5.7 μM) mediated platelet aggregation as compared to losartan (LOS) (collagen, IC 50 = 10.4 μM; CRP-XL, IC 50 = 158 μM; CVX, IC 50 = 11 μM) than any of its enantiomers S ( 6c ) (collagen, IC 50 = 25.3 μM; CRP-XL, IC 50 = 181.4 μM; CVX, IC 50 = 9 μM) and R ( 6d ) (collagen, IC 50 = 126.3 μM; CRP-XL, IC 50 > 500 μM; CVX, IC 50 = 86.8 μM). Compound 6b also inhibited platelet P-selectin expression and thus may diminish atherosclerosis. The molecular interactions of both enantiomers 6c and 6d at the GPVI receptor have been explained through docking studies.
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Bhunia et al. (2016) studied Arterial thrombosis. Compound 6b vs. Losartan was evaluated on Inhibition of collagen, CRP-XL, and convulxin mediated platelet aggregation. Compound 6b showed improved inhibition of collagen, CRP-XL, and convulxin-mediated platelet aggregation compared to losartan, with an in vivo antithrombotic ED50 of 28.36 μmol/kg in mice.
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