RESUMO
Modification of a series of P2Y12 receptor antagonists by replacement of the ester functionality was aimed at minimizing the risk of in vivo metabolic instability and pharmacokinetic variability. The resulting ketones were then optimized for their P2Y12 antagonistic and anticoagulation effects in combination with their physicochemical and absorption profiles. The most promising compound showed very potent antiplatelet action in vivo. However, pharmacodynamic-pharmacokinetic analysis did not reveal a significant separation between its anti-platelet and bleeding effects. The relevance of receptor binding kinetics to the in vivo profile is described.
Assuntos
Plaquetas/efeitos dos fármacos , Fibrinolíticos/farmacologia , Cetonas/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Receptores Purinérgicos P2Y12/metabolismo , Animais , Células CHO , Células CACO-2 , Cricetulus , Cães , Relação Dose-Resposta a Droga , Fibrinolíticos/administração & dosagem , Fibrinolíticos/química , Humanos , Cetonas/administração & dosagem , Cetonas/química , Cinética , Estrutura Molecular , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/química , Relação Estrutura-AtividadeRESUMO
Synthesis and structure-activity relationships of ethyl 6-aminonicotinate acyl sulfonamides, which are potent antagonists of the P2Y12 receptor, are presented. Shifting from 5-chlorothienyl to benzyl sulfonamides significantly increased the potency in the residual platelet count assay. Evaluation of PK parameters in vivo in dog for six compounds showed a 10-fold higher clearance for the azetidines than for the matched-pair piperidines. In a modified Folts model in dog, both piperidine 3 and azetidine 13 dose-dependently induced increases in blood flow and inhibition of ADP-induced platelet aggregation with antithrombotic ED50 values of 3.0 and 10 µg/kg/min, respectively. The doses that induced a larger than 3-fold increase in bleeding time were 33 and 100 µg/kg/min for 3 and 13, respectively. Thus, the therapeutic index (TI) was ≥ 10 for both compounds. On the basis of these data, compound 3 was progressed into human clinical trials as candidate drug AZD1283.