Abstract:

A new series of -disubstituted alkenoic acid derivatives derived from samixogrel 5 were designed and synthesized as combined thromboxane A₂ receptor antagonists/thromboxane A₂ synthase inhibitors with improved solubility and reduced protein binding compared to 5. Hexenoic acid derivatives with a 3-pyridyl group and 3-(2-cyano-3-alkyl-guanidino)phenyl substituent were found to be optimal with regard to this dual mode of action. The most potent compound, E-6-(3-(2-cyano-3-tert-butyl-guanidino)phenyl)-6-(3-pyridyl)hex-5-enoic acid, "terbogrel" 32 inhibits the thromboxane A₂ synthase in human gel-filtered platelets with an IC₅₀ value of 4.0 ± 0.5 nM (n = 4). Radioligand binding studies with ³H-SQ 29,548 revealed that 32 blocks the thromboxane A₂/endoperoxide receptor on washed human platelets with an IC₅₀ of 11 ± 6 nM (n = 2) and with an IC₅₀ of 38 ± 1 nM (n = 15) in platelet-rich plasma. Terbogrel inhibits the collagen-induced platelet aggregation in human platelet-rich plasma and whole blood with an IC₅₀ of 310 ± 18 nM (n = 8) and 52 ± 20 nM (n = 6), respectively. This was shown to translate into a potent antithrombotic effect in vivo as demonstrated in studies using a model of arterial thrombosis in rabbits (ED₅₀ = 0.19 ± 0.07 mg/kg; n = 20). Thus, terbogrel is the first compound with a guanidino moiety demonstrating both a potent TXA₂ synthase inhibition and a potent TXA₂ receptor antagonism and has been selected for further clinical development.