RESUMO
The forearc in Northeast Japan subsided (3-4 mm/year) in the interseismic ~100 years before the 2011 Tohoku earthquake (MW9.1) just like it did during this event. This study attempts to understand the mechanism of the vertical displacement of the forearc during gigantic earthquake cycles via numerical modeling. The results suggest that the interseismic subsidence rate in the forearc increases with the duration of the locking of the asperity of the gigantic earthquake over several hundred years, due to the increasing slip deficit rate on the deeper parts of the plate interface. The increasing slip deficit rate is caused by both the decreasing the shear stress in the shear zone owing to the continuous locking of the asperity and the increasing the mobility of the continental lithosphere owing to the viscoelastic relaxation in the mantle wedge. The deep slip deficit rate extending to ~100 km depth of the plate interface is necessary to explain the observed interseismic forearc subsidence rate. The results also suggest hundreds of years of continuous locking of the asperities of a gigantic earthquake in the western Kuril subduction zone, where fast forearc subsidence has been observed as well.
RESUMO
To identify topically effective EP4 agonists and EP2/EP4 dual agonists with excellent subtype selectivity, further optimization of the 16-phenyl ω-chain moiety of the γ-lactam 5-thia prostaglandin E analog and the 2-mercaptothiazole-4-carboxylic acid analog were undertaken. Rat in vivo evaluation of these newly identified compounds as their poly (lactide-co-glycolide) microsphere formulation, from which sustained release of the test compound is possible, led us to discover compounds that showed efficacy in a rat bone fracture healing model after its topical administration without serious influence on blood pressure and heart rate. A structure-activity relationship study is also presented.
Assuntos
Lactamas/síntese química , Lactamas/farmacologia , Prostaglandinas E Sintéticas/síntese química , Prostaglandinas E Sintéticas/farmacologia , Receptores de Prostaglandina E Subtipo EP2/agonistas , Receptores de Prostaglandina E Subtipo EP4/agonistas , Administração Tópica , Animais , Pressão Sanguínea/efeitos dos fármacos , Células CHO , Cricetinae , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Dinoprostona/química , Avaliação Pré-Clínica de Medicamentos/métodos , Consolidação da Fratura/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Lactamas/administração & dosagem , Masculino , Camundongos , Microesferas , Estrutura Molecular , Poliglactina 910/administração & dosagem , Poliglactina 910/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tiazolidinas/químicaRESUMO
To identify potent EP2/EP4 dual agonists with excellent subtype selectivity, a series of γ-lactam prostaglandin E analogs bearing a 16-phenyl ω-chain were synthesized and evaluated. Structural hybridization of 1 and 2, followed by more detailed chemical modification of the benzoic acid moiety, led us to the discovery of a 2-mercaptothiazole-4-carboxylic acid analog 3 as the optimal compound in the series. An isomer of this compound, the 2-mercaptothiazole-5-carboxylic acid analog 13, showed 34-fold and 13-fold less potent EP2 and EP4 receptor affinities, respectively. Structure activity relationship data from an in vitro mouse receptor binding assay are presented. Continued evaluation in an in vivo rat model of another 2-mercaptothiazole-4-carboxylic acid analog 17, optimized for sustained compound release from PLGA microspheres, demonstrated its effectiveness in a rat bone fracture-healing model following topical administration.
Assuntos
Prostaglandinas Sintéticas/química , Receptores de Prostaglandina E Subtipo EP2/agonistas , Receptores de Prostaglandina E Subtipo EP4/agonistas , Tiazolidinas/química , Administração Tópica , Animais , Células CHO , Cricetinae , Cricetulus , Avaliação Pré-Clínica de Medicamentos , Fraturas Ósseas/tratamento farmacológico , Isomerismo , Camundongos , Prostaglandinas Sintéticas/síntese química , Prostaglandinas Sintéticas/uso terapêutico , Ratos , Receptores de Prostaglandina E Subtipo EP2/genética , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Receptores de Prostaglandina E Subtipo EP4/genética , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Relação Estrutura-Atividade , Tiazolidinas/síntese química , Tiazolidinas/uso terapêuticoRESUMO
A series of γ-lactam prostaglandin E(1) analogs bearing a 16-phenyl moiety in the ω-chain and aryl moiety in the α-chain were synthesized and biologically evaluated. Among the tested compounds, γ-lactam PGE analog 3 designed as a structural hybrid of 1 and 2 was discovered as the most optimized EP2/EP4 dual agonist with excellent subtype-selectivity (K(i) values: mEP2=9.3 nM, mEP4=0.41 nM). A structure-activity relationship study is presented.
Assuntos
Alprostadil/análogos & derivados , Lactamas/química , Receptores de Prostaglandina E Subtipo EP2/química , Receptores de Prostaglandina E Subtipo EP4/química , Animais , Ácidos Carboxílicos/química , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Cinética , Modelos Químicos , Conformação Molecular , RatosRESUMO
A series of novel N-acylsulfonamide analogs were synthesized and evaluated for their binding affinity and antagonist activity for the EP3 receptor subtype. Representative compounds were also evaluated for their inhibitory effect on PGE(2)-induced uterine contraction in pregnant rats. Among those tested, a series of N-acylbenzenesulfonamide analogs were found to be more potent than the corresponding carboxylic acid analogs in both the in vitro and in vivo evaluations. The structure activity relationships (SAR) are also discussed.
Assuntos
Receptores de Prostaglandina E/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Dinoprostona/farmacologia , Descoberta de Drogas , Feminino , Gravidez , Ratos , Receptores de Prostaglandina E Subtipo EP3 , Relação Estrutura-Atividade , Sulfonamidas/química , Contração Uterina/efeitos dos fármacosRESUMO
A series of 3-[2-{[(3-methyl-1-phenylbutyl)amino]carbonyl}-4-(phenoxymethyl)phenyl]propanoic acid analogs were synthesized and evaluated for their in vitro potency. In most cases, introduction of one or two substituents into the two phenyl moieties resulted in the tendency of an increase or retention of in vitro activities. Several compounds, which showed excellent subtype selectivity, were evaluated for their inhibitory effect against PGE(2)-induced uterine contraction in pregnant rats, which is thought to be mediated by the EP3 receptor subtype. The structure-activity relationships (SARs) are also discussed.
Assuntos
Propionatos/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Cricetulus , Feminino , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Gravidez , Propionatos/química , Propionatos/farmacocinética , Ratos , Receptores de Prostaglandina E Subtipo EP3 , Contração Uterina/efeitos dos fármacosRESUMO
A series of N-(p-alkoxy)benzoyl-5-methoxy-2-methylindole-3-acetic acids and N-(p-butoxy)benzoyl-2-methylindole-4-acetic acid were discovered as new chemical leads for a prostaglandin D2 (PGD2) receptor antagonist. Most of them exhibited PGD2 receptor binding and blocked cyclic adenosine 3',5'-monophosphate (cAMP) formation in vitro. In particular, 2-methylindole-4-acetic acid analog 1 showed markedly increased receptor affinity and cAMP antagonist activity. Chemistry and structure activity relationship (SAR) data are also presented.
Assuntos
Ácidos Indolacéticos/síntese química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Animais , Área Sob a Curva , Ligação Competitiva/fisiologia , Células CHO , Cricetinae , AMP Cíclico/antagonistas & inibidores , AMP Cíclico/metabolismo , Meia-Vida , Ácidos Indolacéticos/química , Ácidos Indolacéticos/farmacocinética , Indometacina/análogos & derivados , Indometacina/química , Indometacina/farmacocinética , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Ratos , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Relação Estrutura-AtividadeRESUMO
The process of discovery for highly potent prostaglandin D(2) (PGD(2)) receptor antagonists is reported. A series of N-(p-alkoxy)benzoyl-2-methylindole-4-acetic acids were synthesized and identified as a new class of selective PGD(2) receptor antagonists. Most of them exhibited strong PGD(2) receptor antagonism in binding studies and the cAMP formation assay. The structure-activity relationships (SAR), including subtype selectivity of the synthesized compounds, are also discussed.
Assuntos
Antialérgicos/farmacologia , Ácidos Indolacéticos/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Antialérgicos/síntese química , Sítios de Ligação , AMP Cíclico/metabolismo , Desenho de Fármacos , Ácidos Indolacéticos/química , Relação Estrutura-AtividadeRESUMO
A series of Indomethacin analogs were synthesized and biologically evaluated. Among the compounds tested, N-(p-butoxy)benzoyl-2-methylindole-4-acetic acid 2 was discovered as a new chemical lead for a prostaglandin D2 (PGD2) receptor antagonist. Structure-activity relationship data are also presented.
Assuntos
Antagonistas de Prostaglandina/química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Camundongos , Antagonistas de Prostaglandina/metabolismo , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismoRESUMO
The process of discovering a series of N-(p-alkoxy)benzoyl-2-methylindole-4-acetic acid analogs is presented since these compounds represent a new class of potent, selective, and orally active prostaglandin D2 (PGD2) receptor antagonists. Most of these compounds exhibit strong PGD2 receptor binding and PGD2 receptor antagonism in cAMP formation assays. When given orally, these new antagonists dramatically suppress allergic inflammatory responses, such as the PGD2-induced or OVA-induced increase of vascular permeability. Structure-activity relationship (SAR) data are also discussed.
Assuntos
Antialérgicos/química , Antialérgicos/farmacologia , Ácidos Indolacéticos/química , Ácidos Indolacéticos/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Administração Oral , Animais , Antialérgicos/administração & dosagem , Cobaias , Humanos , Ácidos Indolacéticos/administração & dosagem , Ratos , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismoRESUMO
A series of N-(p-alkoxy)benzoyl-2-methylindole-4-acetic acids were synthesized and evaluated for prostaglandin D(2) (DP) receptor affinity and antagonist activity. Some of them exhibited strong receptor binding and were potent in the cAMP formation assays. These antagonists also suppressed allergic inflammatory responses such as the PGD(2)-induced increase of microvascular permeability. Structure-activity relationship (SAR) data are presented.