RESUMO
A series of 8-methoxy or 8-methylquinolones bearing novel 3-aminooctahydrocyclopenta[c]pyrrole derivatives at the C-7 position was synthesized, and the pharmacological, physicochemical, and toxicological properties of the individual compounds were evaluated. Novel 8-methylquinolone 7, which includes a 3-amino-7-fluorooctahydrocyclopenta[c]pyrrole moiety at the C-7 position, showed potent antibacterial activity against both Gram-positive and negative pathogens. Compound 7 also demonstrated favorable pharmacokinetic and pharmacodynamic properties and an acceptably safe toxicological profile. Consequently, compound 7 was selected as a clinical candidate.
Assuntos
Antibacterianos/farmacologia , DNA Topoisomerases/metabolismo , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Quinolonas/farmacologia , Convulsões/tratamento farmacológico , Inibidores da Topoisomerase/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Células CHO , Cricetulus , Relação Dose-Resposta a Droga , Descoberta de Drogas , Canais de Potássio Éter-A-Go-Go/genética , Canais de Potássio Éter-A-Go-Go/metabolismo , Haplorrinos , Humanos , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinolonas/síntese química , Quinolonas/química , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Distribuição Tecidual , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/químicaRESUMO
Novel 7-[(3 aS,7 aS)-3 a-aminohexahydropyrano[3,4- c]pyrrol-2(3 H)-yl]-6-fluoro-1-[(1 R,2 S)-2- fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 5 (DS21412020) was designed and synthesized to obtain potent antibacterial drugs for the treatment of respiratory tract infections. Compound 5 possessing a trans-fused pyranose ring on the pyrrolidine moiety at the C-7 position of the quinolone scaffold exhibited potent in vitro antibacterial activity against respiratory pathogens, including quinolone-resistant and methicillin-resistant Staphylococcus aureus (QR- MRSA) and quinolone-resistant Escherichia coli (QR- E. coli). Furthermore, compound 5 showed in vivo activity against the experimental murine pneumonia model due to penicillin-resistant Streptococcus pneumoniae ( PRSP) and favorable profiles in preliminary toxicological and nonclinical pharmacokinetic studies. In particular, the reduced lipophilicity and basicity of compound 5 as compared to those of the previously synthesized carba-type compound 4 resulted in a significant reduction in the human ether-a-go-go (hERG) related gene channel inhibition, which have the potential to prolong the QT interval.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Infecções Respiratórias/microbiologia , Animais , Antibacterianos/síntese química , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Farmacorresistência Bacteriana/efeitos dos fármacos , Canal de Potássio ERG1/antagonistas & inibidores , Escherichia coli/efeitos dos fármacos , Feminino , Humanos , Macaca fascicularis , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos Endogâmicos CBA , Testes de Sensibilidade Microbiana , Infecções Pneumocócicas/tratamento farmacológico , Infecções Pneumocócicas/microbiologia , Quinolinas/química , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/patogenicidadeRESUMO
BACKGROUND AND PURPOSE: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that binds to antioxidant response elements located in the promoter region of genes encoding many antioxidant enzymes and phase II detoxifying enzymes. Activation of the Nrf2 pathway seems protective for many organs, and although a well-known Nrf2 activator, bardoxolone methyl, was evaluated clinically for treating chronic kidney disease, it was found to induce adverse events. Many bardoxolone methyl derivatives, mostly derived by chemical modifications, have already been studied. However, we adopted a biotransformation technique to obtain a novel Nrf2 activator. EXPERIMENTAL APPROACH: The potent novel Nrf2 activator, RS9, was obtained from microbial transformation products. Its Nrf2 activity was evaluated by determining NADPH:quinone oxidoreductase-1 induction activity in Hepa1c1c7 cells. We also investigated the effects of RS9 on oxygen-induced retinopathy in rats and glycated albumin-induced blood-retinal barrier permeability in rabbits because many ocular diseases are associated with oxidative stress and inflammation. KEY RESULTS: Bardoxolone methyl doubled the specific activity of Nrf2 in Hepa1c1c7 cells at a much higher concentration than RS9. Moreover, the induction of Nrf2-targeted genes was observed at a one-tenth lower concentration of RS9. Interestingly, the cytotoxicity of RS9 was substantially reduced compared with bardoxolone methyl. Oral and intravitreal administration of RS9 ameliorated the pathological scores and leakage in the models of retinopathy in rats and ocular inflammation in rabbits respectively. CONCLUSION AND IMPLICATIONS: Nrf2 activators are applicable for treating ocular diseases and novel Nrf2 activators have potential as a unique method for prevention and treatment of retinovascular disease.
Assuntos
Barreira Hematorretiniana/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Triterpenos/farmacologia , Animais , Linhagem Celular , Feminino , Produtos Finais de Glicação Avançada , Humanos , Masculino , Camundongos , Oxigênio/toxicidade , Permeabilidade/efeitos dos fármacos , Coelhos , Ratos , Ratos Sprague-Dawley , Retinopatia da Prematuridade/induzido quimicamente , Retinopatia da Prematuridade/patologia , Albumina Sérica/antagonistas & inibidores , Albumina Sérica/toxicidade , Triterpenos/química , Albumina Sérica GlicadaRESUMO
Novel 7-[7-amino-7-methyl-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]- 8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 2a and 2b were designed and synthesized to obtain potent antibacterial drugs for the treatment of respiratory tract infections. Among these, compound 2a possessing (S)-configuration for the asymmetrical carbon on the pyrolidine moiety at the C-7 position of the quinolone scaffold exhibited potent in vitro antibacterial activity against respiratory pathogens including gram-positive (Streptococcus pneumoniae and Staphylococcus aureus), gram-negative (Haemophilus influenzae and Moraxcella catarrhalis), and atypical strains (Chalmydia pneumoniae and Mycoplasma pneumoniae), as well as multidrug-resistant Streptococcus pneumoniae and quinolone-resistant and methicillin-resistant Staphylococcus aureus). Furthermore, compound 2a showed excellent in vivo activity against the experimental murine pneumonia model due to multidrug resistant Streptococcus pneumoniae (MDRSP) and favorable profiles in preliminary toxicological and nonclinical pharmacokinetic studies.
Assuntos
Antibacterianos/farmacologia , Fluoroquinolonas/farmacologia , Quinolonas/farmacologia , Compostos de Espiro/farmacologia , Animais , Antibacterianos/síntese química , Desenho de Fármacos , Fluoroquinolonas/síntese química , Fluoroquinolonas/farmacocinética , Haemophilus influenzae/efeitos dos fármacos , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Quinolonas/síntese química , Quinolonas/farmacocinética , Ratos , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/microbiologia , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacosRESUMO
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
In the early 1990's, we reported on the low-molecular selective fXa inhibitor DX-9065a having two amidino groups. However, it had poor oral bioavailability due to its strong basic amidino groups. To obtain fXa inhibitors with improved oral bioavailability, we investigated various non-amidino fXa inhibitors and finally discovered cis-1,2-diaminocyclohexane derivative 4c to have potent fXa inhibition, promising anticoagulant activity, and good oral bioavailability, compared with amidino compound DX-9065a. In addition, we will discuss the influence of the third substituent on the cyclohexane ring on anti-fXa activity, anticoagulant activity, PK profile, and lipophilicity.
Assuntos
Anticoagulantes/química , Anticoagulantes/farmacologia , Inibidores do Fator Xa , Indóis/farmacologia , Propionatos/farmacologia , Tiazóis/farmacologia , Administração Oral , Animais , Anticoagulantes/síntese química , Disponibilidade Biológica , Cristalografia por Raios X , Fator Xa/metabolismo , Haplorrinos , Humanos , Indóis/química , Indóis/farmacocinética , Naftalenos/síntese química , Naftalenos/química , Naftalenos/farmacologia , Propionatos/síntese química , Propionatos/química , Propionatos/farmacocinética , Ligação Proteica , Tiazóis/química , Tiazóis/farmacocinéticaRESUMO
There have been few reports on synthetic methods for cis-1,2-diaminocyclohexane bearing a third ring substituent. Starting from 3-cyclohexenecarboxylic acid, we developed efficient methods for synthesizing the 3,4-diaminocyclohexanecarboxylic acid derivatives 2-5. We also evaluated their anti-Xa and anticoagulant activities. Among the compounds, acid 2a and amide 2b exhibited the most potent in vitro anti-fXa activity, indicating that the position and stereochemistry of a polar functional group on the cyclohexane ring greatly affected the in vitro anti-fXa activity.
Assuntos
Benzotiazóis/síntese química , Ácidos Carboxílicos/farmacologia , Cicloexilaminas/síntese química , Inibidores do Fator Xa , Animais , Anticoagulantes/farmacologia , Antitrombina III/química , Antitrombina III/farmacologia , Benzotiazóis/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Ácidos Carboxílicos/química , Química Farmacêutica/métodos , Cicloexanos/química , Cicloexilaminas/farmacologia , Desenho de Fármacos , Fator Xa/química , Concentração Inibidora 50 , Modelos Químicos , Inibidores de Serina Proteinase/síntese química , Estereoisomerismo , Fatores de TempoRESUMO
Serine protease factor xa (fXa) inhibitor 1 showed good ex vivo anti-fXa activity upon oral administration in rats. However, it has been revealed that 1 had low metabolic stability against human liver microsomes. To improve the metabolic stability, we attempted to modify the S1 and S4 ligands of 1. These modifications resulted in compound 34b, which exhibited selective anti-fXa activity and excellent anti-coagulation activity.
Assuntos
Anticoagulantes/farmacologia , Antitrombina III , Coagulação Sanguínea/efeitos dos fármacos , Peptídeos/química , Inibidores de Serina Proteinase/farmacologia , Administração Oral , Animais , Anticoagulantes/síntese química , Antitrombina III/síntese química , Antitrombina III/metabolismo , Antitrombina III/farmacologia , Sítios de Ligação , Testes de Coagulação Sanguínea , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Ligantes , Microssomos Hepáticos/metabolismo , Peptídeos/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
Compound 7 was identified as the active metabolite of 6 by HPLC and mass spectral analysis. Modification of lead compound 7 by transformation of its N-oxide 6-6 biaryl ring system and fused aromatics produced a series of non-basic fXa inhibitors with excellent potency in anti-fXa and anticoagulant assays. The optimized compounds 73b and 75b showed sub to one digit micromolar anticoagulant activity (PTCT2). Particularly, anti-fXa activity was detected in plasma of rats orally administered with 1mg/kg of compound 75b.
Assuntos
Anticoagulantes/síntese química , Inibidores do Fator Xa , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/farmacocinética , Administração Oral , Animais , Anticoagulantes/farmacologia , Sítios de Ligação , Coagulação Sanguínea/efeitos dos fármacos , Testes de Coagulação Sanguínea , Desenho de Fármacos , Humanos , Absorção Intestinal , Ratos , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-AtividadeRESUMO
Based on the both of results for X-ray studies of tetrahydrothiazolopyridine derivative 1c and FXV673, we synthesized a series of thiazol-5-ylpyridine derivatives containing pyridine N-oxide and 2-carbamoylthiazole units to optimize the S4 binding element. N-Oxidation of thiazol-5-ylpyridine increased the anti-fXa activity more than 10-fold independent on the position of N-oxide. The 4-pyridine N-oxide derivatives 3a and 3d excelled over the tetrahydrothiazolopyridine 1b in potency. 2-Methylpyridine N-oxide 3d exhibited 49-fold selectivity over thrombin. Our modeling study proposed a binding mode that the pyridine N-oxide ring of 3a stuck into the "cation hole" , and the oxide anion of 3a occupied in the almost same space to that of FXV673. From observations of the SAR and modeling studies, we suggested the possibilities that the formation of hydrogen bond with the oxide anion in the "cation hole" and the affinity of cationic pyridine ring to S4 subsite were responsible for increase in anti-fXa activity.
Assuntos
Óxidos N-Cíclicos/síntese química , Desenho de Fármacos , Inibidores do Fator Xa , Piridinas/síntese química , Inibidores de Serina Proteinase/síntese química , Amidinas/síntese química , Amidinas/farmacologia , Animais , Sítios de Ligação/fisiologia , Óxidos N-Cíclicos/farmacologia , Fator Xa/metabolismo , Humanos , Masculino , Piridinas/farmacologia , Ratos , Ratos Wistar , Inibidores de Serina Proteinase/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologiaRESUMO
Our exploratory study was based on the concept that a non-amidine factor Xa (fXa) inhibitor is suitable for an orally available anticoagulant. We synthesized and evaluated a series of N-(6-chloronaphthalen-2-yl)sulfonylpiperazine derivatives incorporating various fused-bicyclic rings containing an aliphatic amine expected to be S4 binding element. Among this series, 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine type 61 displayed orally potent anti-fXa activity and evident prolongation of prothrombin time (PT) with the moderate bioavailability in rats. The X-ray crystal analysis afforded an obvious binding mode that 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine and 6-chloronaphthalene respectively bound to S4 and S1 subsites. In this X-ray study, we discovered a novel intramolecular S-O close contact. Ab initio energy calculations of model compounds deduced that conformers with the most close S-O proximity were most stable. The Mulliken population analysis proposed that this energy profile was caused by both of electrostatic S-O affinity and N-O repulsion. The results of these calculations and X-ray analysis suggested a possibility that the restricted conformation effected the affinity to S4 subsite of fXa.
Assuntos
Inibidores do Fator Xa , Piridinas/síntese química , Tiazóis/síntese química , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Fator Xa/química , Humanos , Técnicas In Vitro , Masculino , Modelos Moleculares , Conformação Molecular , Ligação Proteica , Tempo de Protrombina , Piridinas/química , Piridinas/farmacologia , Ratos , Ratos Wistar , Tiazóis/química , Tiazóis/farmacologiaRESUMO
In our investigation of factor Xa inhibitors, a series of 1-(6-chloronaphthalen-2-yl)sulfonyl-4-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)piperazines 3a-i were synthesized. In vitro inhibitory activities of the compounds against factor Xa and coagulation are summarized. Among the compounds, 3c and 3d, possessing a carbamoyl or N-methylcarbamoyl moiety, showed potent inhibitory activities when administered orally to rats.
Assuntos
Anticoagulantes/síntese química , Inibidores do Fator Xa , Inibidores de Proteases/síntese química , Piridinas/farmacologia , Administração Oral , Animais , Anticoagulantes/administração & dosagem , Anticoagulantes/farmacologia , Testes de Coagulação Sanguínea , Humanos , Concentração Inibidora 50 , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/farmacologia , Piridinas/síntese química , Ratos , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacologiaRESUMO
Since factor Xa (fXa) plays a pivotal role in the blood coagulation cascade, inhibition of fXa is thought to be an effective treatment for a variety of thrombotic events. (2S)-2-[4-[[(3S)-1-Acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2-naphthyl)propanoic acid hydrochloride pentahydrate (DX-9065a) was previously found in our laboratory as a novel orally active factor Xa inhibitor. DX-9065a exhibits a strong inhibitory activity toward fXa by occupying the substrate recognition (called S1) sites and aryl binding sites of fXa. Herein we describe conversions of the amidinonaphthalene and the acetimidoylpyrrolidine moieties of DX-9065a. Some compounds showed remarkably increased in vitro anti-factor Xa and PRCT activities compared with those of DX-9065a. The most promising compound 38 showed four times the prolongation of APTT against DX-9065a after oral administration to rats.