RESUMO
We have optimized 2-aminomethylphenylamine derivative as a factor Xa inhibitor. Several polar functional groups were introduced in the central phenyl ring, and we focused on zwitter ionic compound showing continuous inhibitory activity in oral administration test. In vitro and oral activities were improved by optimization of S1 and S4 ligands. Incorporating the interaction with S1-ß pocket enhanced in vitro factor Xa inhibitory activity to less than 1 nM. Many zwitter ionic compounds showed long duration of action and potent inhibitory activity and high AUC values in oral administration tests to monkeys.
Assuntos
Anticoagulantes/química , Inibidores do Fator Xa , Inibidores de Serina Proteinase/química , Administração Oral , Compostos de Anilina/síntese química , Compostos de Anilina/química , Compostos de Anilina/farmacocinética , Animais , Anticoagulantes/síntese química , Anticoagulantes/farmacocinética , Sítios de Ligação , Simulação por Computador , Fator Xa/metabolismo , Haplorrinos , Íons/química , Estrutura Terciária de Proteína , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/farmacocinética , Relação Estrutura-AtividadeRESUMO
We previously reported on a series of cyclohexanediamine derivatives as highly potent factor Xa inhibitors. Herein, we describe the modification of the spacer moiety to discover an alternative scaffold. Ethylenediamine derivatives possessing a substituent at the C1 position in S configuration and phenylenediamine derivatives possessing a substituent at the C5 position demonstrated moderate to strong anti-fXa activity. Further SAR studies led to the identification of compound 30 h which showed both good in vitro activity (fXa IC(50) = 2.2 nM, PTCT2 = 3.9 µM) and in vivo antithrombotic efficacy.
Assuntos
Inibidores do Fator Xa , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologia , Cristalografia por Raios X , Desenho de Fármacos , Modelos Moleculares , Inibidores de Serina Proteinase/síntese química , Relação Estrutura-AtividadeRESUMO
We have been researching orally active factor Xa inhibitor for a long time. We explored the new diamine linker using effective ligands to obtain a new attractive original scaffold 2-aminomethylphenylamine derivative. Compound 1D showed very strong in vitro and in vivo factor Xa inhibitory activity, as well as favorable PK profiles in po administration to monkeys.
Assuntos
Compostos de Anilina/química , Compostos de Anilina/síntese química , Inibidores dos Fatores de Coagulação Sanguínea/síntese química , Inibidores do Fator Xa , Animais , Inibidores dos Fatores de Coagulação Sanguínea/química , Cristalografia por Raios X , Haplorrinos , Humanos , Concentração Inibidora 50 , Ligantes , Estrutura Molecular , RatosRESUMO
A series of cis-1,2-diaminocyclohexane derivatives were synthesized with the aim of optimizing previously disclosed factor Xa (fXa) inhibitors. The exploration of 5-6 fused rings as alternative S1 moieties resulted in two compounds which demonstrated improved solubility and reduced food effect compared to the clinical candidate, compound A. Herein, we describe the synthesis and structure-activity relationship (SAR), together with the physicochemical properties and pharmacokinetic (PK) profiles of some prospective compounds.
Assuntos
Anticoagulantes/uso terapêutico , Antitrombina III/uso terapêutico , Cicloexilaminas/uso terapêutico , Desenho de Fármacos , Administração Oral , Sítios de Ligação , Ligação Competitiva , Cristalografia por Raios X , Humanos , Concentração Inibidora 50 , Absorção Intestinal/efeitos dos fármacos , Cinética , Estrutura Molecular , Glicoproteínas da Membrana de Plaquetas , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
A series of cis-1,2-diaminocyclohexane derivatives possessing a 6-6 fused ring for the S1 moiety were synthesized as novel factor Xa (fXa) inhibitors. The synthesis, structure-activity relationship (SAR), and physicochemical properties are reported herein, together with the discovery of compound 45c, which has potent anti-fXa activity, good physicochemical properties and pharmacokinetic (PK) profiles, including a reduced negative food effect.
Assuntos
Anticoagulantes/química , Cicloexilaminas/química , Desenho de Fármacos , Anticoagulantes/farmacologia , Antitrombina III/uso terapêutico , Sítios de Ligação , Cicloexilaminas/farmacologia , Estrutura Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
For the arsenic speciation in marine product samples, two types of pretreatment-analysis combination were compared. One is the combination of solvent extraction and high performance liquid chromatography (HPLC) followed by a highly sensitive arsenic detection, while the other is the combination of alkaline digestion and cryogenic trap (CT) method followed by a highly sensitive arsenic detection. For six certified reference materials (CRMs) of marine animal samples, the concentrations of arsenobetaine (AsB) obtained from the extraction-HPLC method were very consistent with those of trimethylated arsenic species measured by the digestion-CT method. For four seaweed samples, the determination of three arsenosugars (Sugar-1, Sugar-2, and Sugar-3) was favorably carried out by the extraction-HPLC method. Those seaweed samples were also subjected to the digestion-CT method, and the amounts of dimethylated arsenic species measured by the method were approximately equal to the sum of the amounts of dimethylarsinic acid (DMAA) and three arsenosugars (Sugar-1+Sugar-2+Sugar-3) obtained from the extraction-HPLC method.
Assuntos
Arsênio/análise , Alga Marinha/química , Arseniatos/análise , Arsenicais/análise , Ácido Cacodílico/análise , Fracionamento Químico , Cromatografia Líquida de Alta Pressão , Monossacarídeos/análise , Padrões de ReferênciaRESUMO
Previously, we identified cyclohexane diamine derivative 1 as orally bioavailable factor Xa inhibitor. We have investigated two racemic cis-piperidine diamine derivatives 2 and 3 based on 1. Compounds 2a-e showed higher fXa inhibitory activity, anticoagulant activity, and aqueous solubility than 3a-e having same substituent. Compounds 2a, 2c, 2e, and 2g-m having sp2 nitrogen, especially amide and urea derivatives, showed potent anticoagulant activity. Compounds 2h and 2k showed high oral activities in rats.
Assuntos
Inibidores do Fator Xa , Piperidinas/química , Piperidinas/farmacologia , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologia , Administração Oral , Animais , Área Sob a Curva , Diaminas/química , Desenho de Fármacos , Haplorrinos , Humanos , Microssomos Hepáticos/metabolismo , Piperidinas/administração & dosagem , Piperidinas/síntese química , Ratos , Inibidores de Serina Proteinase/administração & dosagem , Inibidores de Serina Proteinase/síntese químicaRESUMO
Exchange of the ethylene tether in a series of pyridopyrimidine-based MexAB-OprM specific efflux pump inhibitors to an amide bond stabilized the olefin of the acrylic acid moiety, preventing facile photoisomerization to the Z-isomer. Furthermore, the activity was drastically improved in the amide tether variants, providing extremely potent acrylic acid and vinyl tetrazole analogues.
Assuntos
Proteínas da Membrana Bacteriana Externa/antagonistas & inibidores , Farmacorresistência Bacteriana/efeitos dos fármacos , Moduladores de Transporte de Membrana , Proteínas de Membrana Transportadoras/antagonistas & inibidores , Pseudomonas aeruginosa/efeitos dos fármacos , Acrilatos/farmacologia , Estabilidade de Medicamentos , Isomerismo , Testes de Sensibilidade Microbiana , Fotoquímica , Pirimidinas/síntese química , Pirimidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
The addition of substituents to the pyridopyrimidine scaffold of MexAB-OprM specific efflux pump inhibitors was explored. As predicted by a pharmacophore model, the incorporation substituents at the 2-position improved potency. Piperidines were found to be optimal, and further introduction of polar groups without compromising the activity was shown to be feasible. Careful positioning of the essential acidic moiety of the pharmacophore relative to the scaffold led to the discovery of vinyl tetrazoles with still greater potency.
Assuntos
Proteínas da Membrana Bacteriana Externa/antagonistas & inibidores , Proteínas de Transporte/antagonistas & inibidores , Moduladores de Transporte de Membrana , Proteínas de Membrana Transportadoras/antagonistas & inibidores , Pseudomonas aeruginosa/fisiologia , Pirimidinas/química , Proteínas da Membrana Bacteriana Externa/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Ligação Proteica/fisiologia , Pseudomonas aeruginosa/química , Pirimidinas/metabolismoRESUMO
The identification of a series of compounds that specifically inhibit efflux by the MexAB-OprM pump system in Pseudomonas aeruginosa is described. Synthesis and in vitro structure-activity relationships (SARs) are outlined. Early leads lacked activity in animal models, and efforts to improve solubility and reduce serum protein binding by the introduction of polar groups are discussed.
Assuntos
Antibacterianos/farmacologia , Proteínas da Membrana Bacteriana Externa/metabolismo , Transporte Biológico Ativo/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/metabolismo , Animais , Antibacterianos/metabolismo , Resistência Microbiana a Medicamentos , Regulação Bacteriana da Expressão Gênica , Lactamas/metabolismo , Camundongos , Testes de Sensibilidade Microbiana , Neutropenia/tratamento farmacológico , Ligação Proteica , Sepse/tratamento farmacológico , Albumina Sérica/metabolismo , Relação Estrutura-AtividadeRESUMO
Problems of low solubility, high serum protein binding, and lack of efficacy in vivo in first generation MexAB-OprM specific efflux pump inhibitors were addressed. Through the use of pharmacophore modelling, the key structural elements for pump inhibition were defined. Use of alternative scaffolds upon which the key elements were arrayed gave second generation leads with greatly improved physical properties and activity in the potentiation of antibacterial quinolones (levofloxacin and sitafloxacin) versus Pseudomonas aeruginosa in vivo.
Assuntos
Antibacterianos/farmacologia , Proteínas da Membrana Bacteriana Externa/metabolismo , Transporte Biológico Ativo/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/metabolismo , Animais , Antibacterianos/metabolismo , Resistência Microbiana a Medicamentos , Fluoroquinolonas/farmacologia , Regulação Bacteriana da Expressão Gênica , Lactamas/metabolismo , Levofloxacino , Camundongos , Testes de Sensibilidade Microbiana , Neutropenia/tratamento farmacológico , Ofloxacino/farmacologia , Ligação Proteica , Ratos , Sepse/tratamento farmacológico , Albumina Sérica/metabolismo , Relação Estrutura-AtividadeRESUMO
Conformational restriction of the ornithine residue of the efflux pump inhibitor D-ornithine-D-homophenylalanine-3-aminoquinoline (MC-02,595, 2) furnished bioisosteric proline derivatives that were less toxic in vivo and as active as the lead in potentiating the activity of the fluoroquinolone levofloxacin via the inhibition of efflux pumps in Pseudomonas aeruginosa.