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1.
J Med Chem ; 60(12): 4932-4948, 2017 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-28537398

RESUMO

BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) enzyme (IC50 3.0 nM) with >10000-fold selectivity over human 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED50 0.12 mg/kg) and in DIO mice. It is orally bioavailable (%F ranges from 20 to 72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans. This ADME profile met our selection criteria for once daily administration, targeting robust inhibition of 11ß-HSD1 enzyme for the first 12 h period after dosing followed by an "inhibition holiday" so that the potential for hypothalamic-pituitary-adrenal (HPA) axis activation might be mitigated. 6n-2 was found to be well-tolerated in phase 1 clinical studies and represents a potential new treatment for type 2 diabetes, metabolic syndrome, and other human diseases modulated by glucocorticoid control.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/análogos & derivados , Azetidinas/farmacologia , Inibidores Enzimáticos/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Actinas/antagonistas & inibidores , Adamantano/administração & dosagem , Adamantano/química , Adamantano/farmacologia , Administração Oral , Animais , Azetidinas/administração & dosagem , Azetidinas/química , Disponibilidade Biológica , Cristalografia por Raios X , Cães , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Feminino , Meia-Vida , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Concentração Inibidora 50 , Macaca fascicularis , Masculino , Camundongos Obesos , Ratos , Relação Estrutura-Atividade
2.
Bioorg Med Chem Lett ; 25(6): 1196-205, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25686852

RESUMO

The design, synthesis and structure-activity relationships of a novel series of 3,4-disubstituted pyrrolidine acid analogs as PPAR ligands is outlined. In both the 1,3- and 1,4-oxybenzyl pyrrolidine acid series, the preferred stereochemistry was shown to be the cis-3R,4S isomer, as exemplified by the potent dual PPARα/γ agonists 3k and 4i. The N-4-trifluoromethyl-pyrimidinyl pyrrolidine acid analog 4i was efficacious in lowering fasting glucose and triglyceride levels in diabetic db/db mice.


Assuntos
Hipoglicemiantes/síntese química , PPAR alfa/agonistas , PPAR gama/agonistas , Pirrolidinas/química , Animais , Glicemia/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Drogas , Feminino , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Ligantes , Camundongos , Camundongos Obesos , PPAR alfa/metabolismo , PPAR gama/metabolismo , Pirrolidinas/síntese química , Pirrolidinas/uso terapêutico , Estereoisomerismo , Relação Estrutura-Atividade , Triglicerídeos/sangue
3.
Bioorg Med Chem Lett ; 24(21): 5045-9, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25266782

RESUMO

A previous disclosure from this lab highlighted the discovery of pyridyl amides as potent 11ß-HSD1 inhibitors. In order to build additional novelty and polarity into this chemotype, replacement of the hydrogen-bonding carbonyl (CO) pharmacophore with the bioisosteric sulfonyl (SO2) group was examined. Despite initial comparisons suggesting the corresponding sulfonamides exhibited weaker activity versus their carbonyl counterparts, further optimization was performed in an effort to identify various potent and unique leads for the program. Judicious incorporation of polar moieties resulted in the identification of compounds with enhanced potency and lipophilicity profiles, resulting in leads with superior aqueous solubility and liver microsomal stability.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos/química , Doenças Metabólicas/tratamento farmacológico , Sulfonamidas/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Sítios de Ligação , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/uso terapêutico , Humanos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Sulfonamidas/metabolismo , Sulfonamidas/uso terapêutico
4.
BMC Gastroenterol ; 14: 133, 2014 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-25066384

RESUMO

BACKGROUND: Although pyogenic liver abscess (PPLA) fatalities are decreasing owing to early diagnosis and effective treatments, PPLA-associated complications still exist. The purpose of this study was to analyze the characteristic features of initial presentations and final outcomes of PPLA caused by different pathogens. METHODS: This retrospective study collected and analyzed information regarding initial presentations and final outcomes in patients diagnosed with PPLA at admitted at Changhua Christian Hospital from January 1 to December 31, 2010. RESULTS: During the study period, we analyzed the records of a total of 134 patients with documented PPLA. There were no significant causative pathogen-related differences in symptoms at initial presentation. Compared with the survivor group, patients in the mortality group were characterized by male gender (p < 0.001), malignancy (p < 0.001), respiratory distress (p =0.007), low blood pressure (p = 0.024), jaundice (p = < 0.001), rupture of liver abscess (p < 0.001), endophthalmitis (p = 0.003), and multiple organ failure (p < 0.001). No patients received liver transplantation or were diagnosed with HIV during the study period. According to univariate logistic regression analysis, gender (OR = 1.185, 95% CI: 0.284-11.130, p = 0.006), malignancy (OR = 2.067, 95% CI: 1.174-13.130, p = 0.004), respiratory distress (OR = 1.667, 95% CI: 1.164-14.210, p = 0.006), low blood pressure (OR = 2.167, 95% CI: 2.104-13.150, p = 0.003), jaundice (OR = 1.9, 95% CI: 1.246-3.297, p = 0.008), rupture of liver abscess (OR = 5.167, 95% CI: 2.194-23.150, p = 0.003), endophthalmitis (OR = 2.167, 95% CI: 1.234-13.140, p = 0.005), and multiple organ failure (OR = 3.067, 95% CI: 1.184-15.150, p = 0.001) differed significantly between the mortality and survivor groups. CONCLUSION: Although the initial presentations of PPLA caused by different pathogens were similar, there were significant differences in mortality in cases involving: (1) male patients, (2) malignancy, (3) initial respiratory distress, (4) initial low blood pressure, (5) jaundice, (6) rupture of liver abscess, (7) endophthalmitis, , and (8) multiple organ failure. We strongly recommend using a severity score of the disease to determine the risk of mortality for each patient with PPLA. In order to prevent complications and reduce mortality, more attention must be paid to high-risk PPLA patients.


Assuntos
Infecções por Escherichia coli/diagnóstico , Infecções por Fusobacterium/diagnóstico , Infecções por Klebsiella/diagnóstico , Abscesso Hepático Piogênico/diagnóstico , Fígado/diagnóstico por imagem , Infecções Estafilocócicas/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Estudos Transversais , Endoftalmite/complicações , Infecções por Escherichia coli/complicações , Infecções por Escherichia coli/mortalidade , Feminino , Infecções por Fusobacterium/complicações , Infecções por Fusobacterium/mortalidade , Humanos , Hipotensão/complicações , Icterícia/complicações , Infecções por Klebsiella/complicações , Infecções por Klebsiella/mortalidade , Abscesso Hepático Piogênico/complicações , Abscesso Hepático Piogênico/mortalidade , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Prognóstico , Radiografia , Síndrome do Desconforto Respiratório do Adulto/complicações , Estudos Retrospectivos , Ruptura Espontânea , Fatores Sexuais , Infecções Estafilocócicas/complicações , Infecções Estafilocócicas/mortalidade , Taiwan , Ultrassonografia , Adulto Jovem
5.
Bioorg Med Chem Lett ; 23(18): 5239-43, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-23927973

RESUMO

In this Letter, we describe the synthesis of several nonamidine analogs of biaryl acid factor VIIa inhibitor 1 containing weakly basic or nonbasic P1 groups. 2-Aminoisoquinoline was found to be an excellent surrogate for the benzamidine group (compound 2) wherein potent inhibition of factor VIIa is maintained relative to most other related serine proteases. In an unanticipated result, the m-benzamide P1 (compounds 21a and 21b) proved to be a viable benzamidine replacement, albeit with a 20-40 fold loss in potency against factor VIIa.


Assuntos
Ácidos Carboxílicos/química , Descoberta de Drogas , Fator VIIa/antagonistas & inibidores , Inibidores de Serino Proteinase/química , Inibidores de Serino Proteinase/farmacologia , Benzamidinas , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Fator VIIa/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Serino Proteinase/síntese química , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 21(22): 6693-8, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21983444

RESUMO

Derived from the HTS hit 1, a series of hydroxyisoquinolines was discovered as potent and selective 11ß-HSD1 inhibitors with good cross species activity. Optimization of substituents at the 1 and 4 positions of the isoquinoline group in addition to the core modifications, with a special focus on enhancing metabolic stability and aqueous solubility, resulted in the identification of several compounds as potent advanced leads.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Isoquinolinas/química , Isoquinolinas/farmacologia , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores Enzimáticos/farmacocinética , Humanos , Isoquinolinas/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Relação Estrutura-Atividade
7.
J Med Chem ; 53(7): 2854-64, 2010 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-20218621

RESUMO

An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) alpha agonist, with an EC(50) of 10 nM for human PPARalpha and approximately 410-fold selectivity vs human PPARgamma in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPARdelta. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPARalpha ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPARalpha in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.


Assuntos
Descoberta de Drogas , Glicina/análogos & derivados , Oxazóis/química , Oxazóis/farmacologia , PPAR alfa/agonistas , Animais , Linhagem Celular , Cricetinae , Cristalografia por Raios X , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Glicina/síntese química , Glicina/química , Glicina/farmacologia , Glicina/toxicidade , Humanos , Masculino , Camundongos , Modelos Moleculares , Oxazóis/síntese química , Oxazóis/toxicidade , PPAR alfa/química , PPAR alfa/genética , Estrutura Terciária de Proteína , Especificidade por Substrato , Ativação Transcricional/efeitos dos fármacos
8.
Bioorg Med Chem Lett ; 18(11): 3168-72, 2008 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-18485702

RESUMO

Several series of pyridine amides were identified as selective and potent 11beta-HSD1 inhibitors. The most potent inhibitors feature 2,6- or 3,5-disubstitution on the pyridine core. Various linkers (CH(2)SO(2), CH(2)S, CH(2)O, S, O, N, bond) between the distal aryl and central pyridyl groups are tolerated, and lipophilic amide groups are generally favored. On the distal aryl group, a number of substitutions are well tolerated. A crystal structure was obtained for a complex between 11beta-HSD1 and the most potent inhibitor in this series.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Amidas/química , Técnicas de Química Combinatória , Cristalografia por Raios X , Desenho de Drogas , Humanos , Concentração Inibidora 50 , Conformação Molecular , Estrutura Molecular , Piridinas/química , Relação Estrutura-Atividade
9.
Biochim Biophys Acta ; 1774(9): 1184-91, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17707701

RESUMO

11beta-hydroxysteroid dehydrogenase 1 regulates the tissue availability of cortisol by interconverting cortisone and cortisol. It is capable of functioning as both a reductase and a dehydrogenase depending upon the surrounding milieu. In this work, we have studied the reaction mechanism of a soluble form of human 11beta-hydroxysteroid dehydrogenase 1 and its mode of inhibition by potent and selective inhibitors belonging to three different structural classes. We found that catalysis follows an ordered addition with NADP(H) binding preceding the binding of the steroid. While all three inhibitors tested bound to the steroid binding pocket, they differed in their interactions with the cofactor NADP(H). Compound A, a pyridyl amide bound more efficiently to the NADPH-bound form of 11beta-hydroxysteroid dehydrogenase 1. Compound B, an adamantyl triazole, was unaffected by NADP(H) binding and the sulfonamide, Compound C, showed preferential binding to the NADP+ -bound form of 11beta-hydroxysteroid dehydrogenase 1. These differences were found to augment significant selectivity towards inhibition of the reductase reaction versus the dehydrogenase reaction. This selectivity may translate to differences in the in vivo effects of 11beta-hydroxysteroid dehydrogenase 1 inhibitors.


Assuntos
11-beta-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenases/metabolismo , Piridinas/farmacologia , Sulfonamidas/farmacologia , Triazóis/farmacologia , Humanos , Cinética , NADP/metabolismo
10.
J Med Chem ; 50(13): 2967-80, 2007 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-17536795

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/farmacologia
11.
Acta Anaesthesiol Taiwan ; 45(1): 15-20, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17424754

RESUMO

BACKGROUND: Infraclavicular brachial plexus block has been widely used for surgical procedures below the mid humerus owing to its excellent anesthetic quality and ease of practice. However, what is the optimal upper arm position for carrying out the procedure still lacks consensus of opinion. The primary goal of this study was to determine the optimal upper arm position for coracoid infraclavicular block by ultrasonographic examination. METHODS: High-frequency (5-10 MHz) ultrasonographic examination on the vertical line 2 cm medial to the coracoid process was performed in 40 volunteers. We assessed the influence of four different upper arm positions on the topographic anatomy of the infraclavicular region. Ultrasonography-derived distances and morphometric measurements were applied to evaluate the optimal puncture site. The deviation of coracoid puncture site from the ultrasonographically modified ideal puncture site in distance was also recorded. RESULTS: When the upper arm was abducted 900, the brachial plexus was much closer to the skin (1.67 cm) and farther from the pleura (1.15 cm) as compared with other positions. In this position, the revealation of anterosuperior plexus relative to artery, identification of all three cords and pleura were 53.8%, 64.1% and 87.2%, respectively. We also found that as the upper arm was drawing from abduction to adduction the ideal puncture site tended to shift more inferiorly. CONCLUSIONS: We recommend the most optimal position for carrying out coracoid infraclavicular brachial plexus block is to abduct the upper arm 90 degrees with external rotation of the shoulder. Though ultrasonographic guidance is suggested for infraclaricular brachial plexus block, an optimal position for puncture site determined by anatomical landmark is also acceptable.


Assuntos
Plexo Braquial , Bloqueio Nervoso/métodos , Ombro/diagnóstico por imagem , Adulto , Braço , Feminino , Humanos , Masculino , Bloqueio Nervoso/efeitos adversos , Pneumotórax/etiologia , Postura , Ombro/anatomia & histologia , Ultrassonografia
12.
Drug Metab Dispos ; 34(3): 427-39, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16381667

RESUMO

The metabolism and disposition of 14C-labeled muraglitazar (Pargluva), a novel dual alpha/gamma peroxisome proliferator-activated receptor activator, was investigated in eight healthy male subjects with and without bile collection (groups 1 and 2) after a single 20-mg oral dose. Bile samples were collected for 3 to 8 h after dosing from group 2 subjects in addition to the urine and feces collection. In plasma, the parent compound was the major component, and circulating metabolites, including several glucuronide conjugates, were minor components at all time points. The exposure to parent drug (Cmax and area under the plasma concentration versus time curve) in subjects with bile collection was generally lower than that in subjects without bile collection. The major portion of the radioactive dose was recovered in feces (91% for group 1 and 51% for group 2). In addition, 40% of the dose was recovered in the bile from group 2 subjects. In this 3- to 8-h bile, the glucuronide of muraglitazar (M13, 15% of dose) and the glucuronides of its oxidative metabolites (M17a,b,c, M18a,b,c, and M20, together, 16% of dose) accounted for approximately 80% of the biliary radioactivity; muraglitazar and its O-demethylated metabolite (M15) each accounted for approximately 4% of the dose. In contrast, fecal samples only contained muraglitazar and its oxidative metabolites, suggesting hydrolysis of biliary glucuronides in the intestine before fecal excretion. Thus, the subjects with and without bile collection showed different metabolic profiles of muraglitazar after oral administration, and glucuronidation was not observed as a major pathway of metabolic clearance from subjects with the conventional urine and fecal collection, but was found as a major elimination pathway from subjects with bile collection.


Assuntos
Bile/química , Glucuronídeos/metabolismo , Glicina/análogos & derivados , Oxazóis/farmacocinética , Radioisótopos de Carbono , Glicina/sangue , Glicina/química , Glicina/farmacocinética , Glicina/urina , Humanos , Masculino , Taxa de Depuração Metabólica , Desintoxicação Metabólica Fase II , Estrutura Molecular , Oxazóis/sangue , Oxazóis/química , Oxazóis/urina , PPAR alfa/agonistas , PPAR gama/agonistas
13.
Drug Metab Dispos ; 34(2): 267-80, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16280454

RESUMO

Muraglitazar (Pargluva), a dual alpha/gamma peroxisome proliferator-activated receptor activator, is currently in clinical development for treatment of type 2 diabetes. This study describes the structural elucidation of the human oxidative metabolites of muraglitazar through the use of a combination of microbial bioreactors, NMR and accurate mass analyses, and organic synthesis. Plasma, urine, and feces were collected from six healthy subjects following oral administration of 14C-labeled muraglitazar (10 mg, 100 microCi) and pooled samples were analyzed. Approximately 96% of the recovered radioactive dose was found in the feces and 3.5% in the urine. The parent compound represented >85% of the radioactivity in plasma. The fecal radioactivity was distributed among 16 metabolites (M1-M12, M14-M16, and M8a) and the parent drug, of which hydroxylation and O-demethylation metabolites (M5, M10, M11, M14, and M15) represented the prominent human metabolites. The urinary radioactivity was distributed into several peaks including muraglitazar glucuronide (M13) and the parent drug. Low concentrations of metabolites in human samples prevented direct identification of metabolites beyond liquid chromatographic (LC)-mass spectrometric analysis. Microbial strains Cunninghamella elegans and Saccharopolyspora hirsuta produced muraglitazar metabolites that had the same high performance liquid chromatography retention times and the same tandem mass spectrometric (MS/MS) properties as the corresponding human metabolites. The microbial metabolites M9, M10, M11, M14, M15, and M16 were isolated and analyzed by NMR. Based on these LC-MS/MS and NMR analyses, and organic synthesis, the structures of 16 human oxidative metabolites were identified. The oxidative metabolism of muraglitazar was characterized by hydroxylation, O-demethylation, oxazolering opening, and O-demethylation/hydroxylation, as well as O-dealkylation and carboxylic acid formation. This study demonstrated the utility of microbial bioreactors for the identification of metabolites.


Assuntos
Cunninghamella/metabolismo , Glicina/análogos & derivados , Oxazóis/farmacocinética , Saccharopolyspora/metabolismo , Reatores Biológicos , Biotransformação , Fezes/química , Glicina/sangue , Glicina/metabolismo , Glicina/farmacocinética , Glicina/urina , Humanos , Oxazóis/sangue , Oxazóis/metabolismo , Oxazóis/urina , Oxirredução , PPAR alfa/agonistas , PPAR gama/agonistas
14.
Bioorg Med Chem Lett ; 14(1): 177-80, 2004 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-14684323

RESUMO

Inhibition of the sodium hydrogen exchanger isoform-1 (NHE-1) has been shown to limit damage to the myocardium under ischemic conditions in animals. While most known NHE-1 inhibitors are acylguanidines, this report describes the design and synthesis of a series of heterocyclic inhibitors of NHE-1 including aminoimidazoles with undiminished in vitro activity and oral bioavailability.


Assuntos
Proteínas de Transporte de Cátions/antagonistas & inibidores , Guanidinas/administração & dosagem , Imidazóis/administração & dosagem , Proteínas de Membrana/antagonistas & inibidores , Trocadores de Sódio-Hidrogênio/antagonistas & inibidores , Administração Oral , Disponibilidade Biológica , Proteínas de Transporte de Cátions/metabolismo , Linhagem Celular , Guanidinas/química , Guanidinas/farmacocinética , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Proteínas de Membrana/metabolismo , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Trocador 1 de Sódio-Hidrogênio , Trocadores de Sódio-Hidrogênio/metabolismo , Estereoisomerismo
15.
Bioorg Med Chem Lett ; 13(3): 507-11, 2003 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-12565961

RESUMO

Compound 1 was identified by high throughput screening as a novel, potent, non-amidine factor Xa inhibitor with good selectivity against thrombin and trypsin. A series of modifications of the three aromatic groups of 1 was investigated. Substitution of chlorine or bromine for fluorine on the aniline ring led to the discovery of subnanomolar factor Xa inhibitors. Positions on the anthranilic acid ring that can accommodate further substitution were also identified.


Assuntos
Inibidores do Fator Xa , Tiofenos/farmacologia , ortoaminobenzoatos/farmacologia , Animais , Anticoagulantes/síntese química , Anticoagulantes/farmacologia , Bovinos , Compostos Heterocíclicos/farmacologia , Humanos , Indicadores e Reagentes , Cinética , Tempo de Protrombina , Inibidores de Serino Proteinase/farmacologia , Relação Estrutura-Atividade , Tiofenos/química , Trombina/antagonistas & inibidores , Inibidores da Tripsina/síntese química , Inibidores da Tripsina/farmacologia , ortoaminobenzoatos/química
16.
J Med Chem ; 45(12): 2484-93, 2002 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-12036356

RESUMO

A novel series of diaryloxypyridines have been designed as selective nanomolar factor Xa (fXa) inhibitors for use as anticoagulants. In this paper, we describe our efforts to identify an additional interaction and a replacement for the distal amidine group that binds in the S3/S4 pocket of fXa. Introduction of a hydroxyl group para to the proximal amidine group increases the potency vs fXa by 1-2 orders of magnitude, which is the result of a hydrogen bond to Ser195 of the catalytic triad. A methyl imidazoline and a dimethylamide are good alternatives for the second amidine. These substitutions have increased the selectivity vs the related serine proteases trypsin and thrombin. The synthesis, in vitro activity, and hypothetical modes of binding to fXa based on trypsin crystallographic data are outlined.


Assuntos
Amidinas/síntese química , Inibidores do Fator Xa , Inibidores de Serino Proteinase/síntese química , Amidinas/química , Amidinas/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Fator Xa/química , Humanos , Modelos Moleculares , Ratos , Inibidores de Serino Proteinase/química , Inibidores de Serino Proteinase/farmacocinética , Relação Estrutura-Atividade , Trombina/química , Tripsina/química
17.
Bioorg Med Chem Lett ; 12(9): 1307-10, 2002 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-11965377

RESUMO

A novel potent and selective aminophenol scaffold for fXa inhibitors was developed from a previously reported benzimidazole-based naphthylamidine template. The aminophenol template is more synthetically accessible than the benzimidazole template, which simplified the introduction of carboxylic acid groups. Substitution of a propenyl-para-hydroxy-benzamidine group on the aminophenol template produced selective, sub-nanomolar fXa inhibitors. The potency of the inhibitors is partially explained with the aid of a trypsin complex crystal structure.


Assuntos
Aminofenóis/química , Aminofenóis/síntese química , Inibidores do Fator Xa , Inibidores de Serino Proteinase/química , Inibidores de Serino Proteinase/síntese química , Difração de Raios X
18.
Bioorg Med Chem Lett ; 12(9): 1311-4, 2002 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-11965378

RESUMO

Optimization of the benzimidazole-based fXa inhibitors for selectivity versus thrombin and trypsin was achieved by substitution on the benzimidazole ring and replacement of the naphthylamidine group. Substitution of a nitro group at the 4-position on the benzimidazole improves both potency against fXa and selectivity versus thrombin. Alternatively, replacement of the naphthylamidine with either a biphenylamidine or propenylbenzamidine not only improves fXa potency and selectivity versus thrombin, but selectivity versus trypsin as well.


Assuntos
Benzimidazóis/química , Inibidores do Fator Xa , Inibidores de Serino Proteinase/química , Trombina/metabolismo , Tripsina/metabolismo , Benzimidazóis/metabolismo , Inibidores de Serino Proteinase/metabolismo
19.
Bioorg Med Chem ; 10(3): 657-66, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11814853

RESUMO

A novel series of triaryloxypyridines have been designed to inhibit factor Xa, a serine protease strategically located in the coagulation cascade. Inhibitor 5e has a K(I) against factor Xa of 0.12nM and is greater than 8000- and 2000-fold selective over two related serine proteases, thrombin and trypsin, respectively. The 4-position of the central pyridine has been identified as a site that tolerates various substitutions without deleterious effects on potency and selectivity. This suggests that the 4-position of the pyridine ring is an ideal site for chemical modifications to identify inhibitors with improved pharmacokinetic characteristics. This investigation has resulted in inhibitor 5d, which has an oral availability of 6% in dogs. The synthesis, in vitro activity, and in vivo profile of this class of inhibitors is outlined.


Assuntos
Inibidores do Fator Xa , Piridinas/síntese química , Inibidores de Serino Proteinase/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Bovinos , Cães , Desenho de Drogas , Fibrinolíticos/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Inibidores de Serino Proteinase/farmacocinética , Inibidores de Serino Proteinase/farmacologia , Relação Estrutura-Atividade
20.
J Air Waste Manag Assoc ; 49(8): 894-905, 1999 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28060630

RESUMO

This work presents a novel two-reservoir model to simulate, for a pulse-jet cleaning system, the air discharged from an air reservoir via a diaphragm valve to a blowpipe and ultimately into the atmosphere. The air reservoir and blowpipe are referred to reservoir 1 and reservoir 2, respectively. The proposed model consists of (1) a set of governing equations that are solved by a finite difference and (2) an iterative calculation method to describe the physical phenomena. The feasibility of the proposed model is also evaluated via experiments performed herein. Comparing the mass flow rates predicted by the proposed model with those of the benchmark solutions reveals that the model predictions are about 10% overestimated. In addition, the proposed model is more accurately simulated by considering the friction effects induced by the exit of the air reservoir and the nozzles on the blowpipe. The former increases the Mach number of the air and equals that of a frictional pipe of 4fLe/Dh . The latter decreases the mass flow rate discharged from the nozzles. A discharge coefficient Cdn is introduced to represent the ratio of the mass flow rate discharged from a real nozzle and an ideal one. Moreover, experimental methods are developed to determine the values of 4fLe/Dh and Cdn. When the parameters of 4fLe/Dh and Cdn were included in the model, the accuracy of the model predictions was significantly improved. The deviations between the mass flow rates of the model predictions and the bench mark solutions were markedly reduced to 3%.

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