RESUMEN
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.
Asunto(s)
Permeabilidad Capilar/efectos de los fármacos , Indoles/química , Indoles/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/antagonistas & inhibidores , Receptores de Prostaglandina/metabolismo , Animales , Células CHO , Conjuntiva/irrigación sanguínea , Cricetinae , Cricetulus , Descubrimiento de Drogas , Cobayas , HumanosRESUMEN
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.
Asunto(s)
Propionatos/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Animales , Células CHO , Cricetinae , Cricetulus , Femenino , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Embarazo , Propionatos/química , Propionatos/farmacocinética , Ratas , Subtipo EP3 de Receptores de Prostaglandina E , Contracción Uterina/efectos de los fármacosRESUMEN
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.
Asunto(s)
Antialérgicos/farmacología , Ácidos Indolacéticos/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Antialérgicos/síntesis química , Sitios de Unión , AMP Cíclico/metabolismo , Diseño de Fármacos , Ácidos Indolacéticos/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antialérgicos/química , Antialérgicos/farmacología , Ácidos Indolacéticos/química , Ácidos Indolacéticos/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Administración Oral , Animales , Antialérgicos/administración & dosificación , Cobayas , Humanos , Ácidos Indolacéticos/administración & dosificación , Ratas , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismoRESUMEN
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.