RESUMO
A series of N-benzoyl-2-methylindole-3-acetic acids were synthesized and biologically evaluated as prostaglandin (PG) D2 receptor antagonists. Some of the selected compounds significantly inhibited OVA-induced vascular permeability in guinea pig conjunctiva after oral dosing. Structure-activity relationship study is presented.
Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Indóis/química , Indóis/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/antagonistas & inibidores , Receptores de Prostaglandina/metabolismo , Animais , Células CHO , Túnica Conjuntiva/irrigação sanguínea , Cricetinae , Cricetulus , Descoberta de Drogas , Cobaias , HumanosRESUMO
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
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
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.
