RESUMEN
Novel benzo[b]thiophene diamine thrombin inhibitors were investigated, focusing on a contracted C4'-side chain series. SAR studies identified compounds with either a pyrrolidino or morpholino group as potent, active site directed thrombin inhibitors when the amino group was connected to the C3-phenyl ring with a methylene linker at the C4' position of the phenyl ring.
Asunto(s)
Antitrombinas/química , Antitrombinas/farmacología , Tiofenos/química , Tiofenos/farmacología , Relación Estructura-ActividadRESUMEN
A systematic investigation of the structure-activity relationships of the C-3 side chain of the screening hit 1a led to the identification of the potent thrombin inhibitors 23c, 28c, and 31c. Their activities (1240, 903, and 1271 x 10(6) L/mol, respectively) represent 2200- and 2900-fold increases in potency over the starting lead 1a. This activity enhancement was accomplished with an increase of thrombin selectivity. The in vitro anticoagulant profiles of derivatives 28c and 31c were determined, and they compare favorably with the clinical agent H-R-1-[4aS, 8aS]perhydroisoquinolyl-prolyl-arginyl aldehyde (D-Piq-Pro-Arg-H; 32). The more potent members of this series have been studied in an arterial/venous shunt (AV shunt) model of thrombosis and were found to be efficacious in reducing clot formation. However, their efficacy is currently limited by their rapid and extensive distribution following administration.
Asunto(s)
Anticoagulantes/síntesis química , Pirrolidinas/síntesis química , Inhibidores de Serina Proteinasa/síntesis química , Tiofenos/síntesis química , Trombina/antagonistas & inhibidores , Animales , Anticoagulantes/química , Anticoagulantes/farmacocinética , Anticoagulantes/farmacología , Sitios de Unión , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Humanos , Técnicas In Vitro , Modelos Moleculares , Pirrolidinas/química , Pirrolidinas/farmacocinética , Pirrolidinas/farmacología , Ratas , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacocinética , Inhibidores de Serina Proteinasa/farmacología , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacocinética , Tiofenos/farmacología , Trombosis/sangre , Trombosis/metabolismoRESUMEN
A novel series of benzo[b]thiophene diamine thrombin inhibitors with a conformationally restricted C3-side chain 3 was investigated. The constrained C3-side chain by a cyclohexyl ring contributed to not only an additive but also a synergistic effect on the thrombin inhibitory activity. The SAR studies resulted in the discovery of a potent thrombin inhibitor 27 that was over 750-fold more potent than the initial lead compound 1.
Asunto(s)
Tiofenos/química , Trombina/antagonistas & inhibidores , Relación Estructura-Actividad , Tiofenos/farmacologíaRESUMEN
Potent, subnanomolar thrombin inhibitors 4, 5, and 6 are developed through side chain optimization of novel, benzo[b]thiophene-based small organic entities 2 and 3 and through SAR additivity studies of the new structural elements identified. X-ray crystallographic studies of 4b-thrombin complex revealed a hydrophobic and an electrostatic interaction of these new elements with thrombin at the S2 and S3 binding sites. In vitro and in vivo pharmacological studies showed that 4, 5, and 6 are potent anticoagulants in human plasma with demonstrated antithrombotic efficacy in a rat model of thrombosis.
Asunto(s)
Tiofenos/química , Trombina/antagonistas & inhibidores , Animales , Anticoagulantes/química , Anticoagulantes/farmacología , Anticoagulantes/uso terapéutico , Sitios de Unión , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Humanos , Modelos Moleculares , Ratas , Relación Estructura-Actividad , Tiofenos/farmacología , Tiofenos/uso terapéutico , Trombina/química , Trombosis/tratamiento farmacológicoRESUMEN
Synthesis and initial in vitro evaluation of a novel series of phenyl oxazole derivatives are described. An SAR study of the novel dual-acting TRA/TSI agent has revealed that the lipophilicity of the oxazole amide substituents greatly influences the TRA activity but not the TSI. The chain length of the alkenoic acid side chain affects both TRA and TSI. The optimal chain length for the combined activities was found to be n = 4 (heptenoic acid).
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Receptores de Tromboxanos/antagonistas & inhibidores , Tromboxano-A Sintasa/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Relación Estructura-ActividadRESUMEN
A novel series of oxazolecarboxamide-substituted omega-phenyl-omega-(3-pyridyl)alkenoic acid derivatives was discovered as potent dual-acting agents to block the TXA2 receptor and to inhibit the thromboxane synthase (TRA/TSI). Synthesis, structure-activity relationship (SAR), and in vitro and in vivo pharmacology of this series of compounds are described. Modification of the series revolved around the oxazole moiety to increase the hydrophilicity of the compounds and to correlate the biological activity with lipophilicity of the compounds. The most potent in the series was (E)-7-[4-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl] phenyl]-7 -(3-pyridyl)hept-6-enoic acid (14) with Kd = 9.9 +/- 0.4 nM for the thromboxane receptor antagonism and IC50 = 55.0 +/- 17.9 nM for thromboxane synthase inhibition. The compound 14 was a selective TRA/TSI which exhibited desirable characteristics for oral activity, "shunt" effect to elevate PGI2 level, and absence of agonist activity.