RESUMO
Novel plasminogen activator inhibitor-1 (PAI-1) inhibitors with highly improved oral bioavailability were discovered by structure-activity relationship studies on N-acyl-5-chloroanthranilic acid derivatives. Because lipophilic N-acyl groups seemed to be important for the anthranilic acid derivatives to strongly inhibit PAI-1, synthesis of compounds in which 5-chloroanthranilic acid was bound to a variety of highly lipophilic moieties with appropriate linkers was investigated. As the result it appeared that some of the derivatives possessing aryl- or heteroaryl-substituted phenyl groups in the acyl chain had potent in vitro PAI-1 inhibitory activity. Oral absorbability of typical compounds was also evaluated in rats, and compounds 40, 55, 60 and 76 which have diverse chemical structure with each other were selected for further pharmacological evaluation.
Assuntos
Anticoagulantes/farmacologia , Inibidor 1 de Ativador de Plasminogênio/farmacologia , ortoaminobenzoatos/farmacologia , Administração Oral , Animais , Anticoagulantes/administração & dosagem , Anticoagulantes/síntese química , Anticoagulantes/farmacocinética , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Masculino , Estrutura Molecular , Ratos Wistar , Relação Estrutura-Atividade , ortoaminobenzoatos/administração & dosagem , ortoaminobenzoatos/síntese química , ortoaminobenzoatos/farmacocinéticaRESUMO
Novel anthranilic acid derivatives having substituted N-acyl side chains were designed and synthesized for evaluation as plasminogen activator inhibitor-1 (PAI-1) inhibitors. Compounds with a 4-diphenylmethyl-1-piperazinyl moiety on the acyl side chains in general exhibited potent in vitro PAI-1 inhibitory activity and good pharmacokinetic profiles after oral administration in rats. Compound 16f (TM5275) was identified as a promising candidate for further pharmacological evaluation.
Assuntos
Inibidor 1 de Ativador de Plasminogênio/administração & dosagem , Inibidor 1 de Ativador de Plasminogênio/química , ortoaminobenzoatos/administração & dosagem , ortoaminobenzoatos/química , Administração Oral , Animais , Humanos , Masculino , Inibidor 1 de Ativador de Plasminogênio/farmacocinética , Ratos , Ratos Wistar , Relação Estrutura-Atividade , ortoaminobenzoatos/farmacocinéticaRESUMO
Small molecule inhibitors of plasminogen activator inhibitor (PAI)-1 have been reported to date but their clinical effects still remain unknown. The present study was undertaken to investigate the structure-activity relationships (SAR) of newly synthesized 2-acylamino-3-thiophenecarboxylic acid dimers based upon a core structure of TM5001 (1) and TM5007 (2) that we have previously identified as orally effective PAI-1 inhibitors. In general, compounds possessing bulky or/and hydrophobic substituents (e.g. phenyl, isobutyl group) on the both thiophene rings showed potent PAI-1 inhibitory activities irrespective of the positions of the substitution. The mono-carboxyl derivative (10) exhibited PAI-1 inhibition comparable to the corresponding dicarboxyl compound (9f).
Assuntos
Aminas/química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Inibidor 1 de Ativador de Plasminogênio/química , Inibidor 1 de Ativador de Plasminogênio/farmacologia , Tiofenos/química , Acilação , Ácidos Carboxílicos/síntese química , Dimerização , Humanos , Estrutura Molecular , Inibidor 1 de Ativador de Plasminogênio/síntese química , Relação Estrutura-AtividadeRESUMO
Inhibition of plasminogen activator inhibitor (PAI)-1 is useful to treat several disorders including thrombosis. An inhibitor of PAI-1 (TM5275) was newly identified by an extensive study of structure-activity relationship based on a lead compound (TM5007) which was obtained through virtual screening by docking simulations. Its antithrombotic efficacy and adverse effects were tested in vivo in rats and nonhuman primates (cynomolgus monkey). TM5275, administered orally in rats (1 to 10 mg/kg), has an antithrombotic effect equivalent to that of ticlopidine (500 mg/kg) in an arterial venous shunt thrombosis model and to that of clopidogrel (3 mg/kg) in a ferric chloride-treated carotid artery thrombosis model. TM5275 does not modify activated partial thromboplastin time and prothrombin time or platelet activity and does not prolong bleeding time. Combined with tissue plasminogen activator, TM5275 improves the latter's therapeutic efficacy and reduces its adverse effect. Administered to a monkey model of photochemical induced arterial thrombosis, TM5275 (10 mg/kg) has the same antithrombotic effect as clopidogrel (10 mg/kg), without enhanced bleeding. This study documents the antithrombotic benefits of a novel, more powerful, PAI-1 inhibitor in rats and, for the first time, in nonhuman primates. These effects are obtained without adverse effect on bleeding time.