RESUMO
There remains a high unmet medical need for a safe oral therapy for thrombotic disorders. The serine protease factor Xa (fXa), with its central role in the coagulation cascade, is among the more promising targets for anticoagulant therapy and has been the subject of intensive drug discovery efforts. Investigation of a hit from high-throughput screening identified a series of thiophene-substituted anthranilamides as potent nonamidine fXa inhibitors. Lead optimization by incorporation of hydrophilic groups led to the discovery of compounds with picomolar inhibitory potency and micromolar in vitro anticoagulant activity. Based on their high potency, selectivity, oral pharmacokinetics, and efficacy in a rat venous stasis model of thrombosis, compounds ZK 814048 (10b), ZK 810388 (13a), and ZK 813039 (17m) were advanced into development.
Assuntos
Amidas/síntese química , Aminopiridinas/síntese química , Anticoagulantes/síntese química , Inibidores do Fator Xa , Tiofenos/síntese química , ortoaminobenzoatos/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Cristalografia por Raios X , Cães , Humanos , Técnicas In Vitro , Masculino , Modelos Moleculares , Tempo de Protrombina , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Tiofenos/farmacocinética , Tiofenos/farmacologia , Trombose Venosa/tratamento farmacológico , ortoaminobenzoatos/farmacocinética , ortoaminobenzoatos/farmacologiaRESUMO
A series of thiophene-containing non-amidine factor Xa inhibitors is described. Simple methyl-substituted thiophene analogs were relatively weak inhibitors. However, introduction of hydrophilic substituents at C-4 or C-5 of the thiophene afforded inhibitors with low nanomolar potency. Optimization of the thiophene substituent at C-4 afforded subnanomolar inhibitors with improved in vitro anticoagulant activity. Incorporating basic amine substituents on the thiophene increased hydrophilicity and improved anticoagulant activity. The pharmacokinetic profile of one inhibitor was evaluated in dogs, and the X-ray crystal structure of this compound bound to factor Xa provides insight into the observed SAR for binding to factor Xa.
Assuntos
Amidas/farmacologia , Inibidores do Fator Xa , Inibidores de Serina Proteinase/farmacologia , Tiofenos/química , Amidas/química , Animais , Cristalografia por Raios X , Cães , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Modelos Moleculares , Inibidores de Serina Proteinase/farmacocinética , Relação Estrutura-AtividadeRESUMO
[reaction: see text] The fluorescence emission intensity of the dansyl group is significantly diminished upon appending an ethyldimethylamino group to the N1 nitrogen substituent. Addition of acids and metal ions (i.e., Zn(2+)) to solutions of trimethylethylenediamine naphthalene sulfonamide (trinsyl) 2 produces a >25-fold increase in fluorescence intensity. Trinsyl probe 2 has been used as a diagnostic for the diffusion of protons and metal ions in a network polymer as well as an optical reporter for the glass transition temperature.