RESUMEN
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.
Asunto(s)
Ácidos Indolacéticos/síntesis química , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Animales , Área Bajo la Curva , Unión Competitiva/fisiología , Células CHO , Cricetinae , AMP Cíclico/antagonistas & inhibidores , AMP Cíclico/metabolismo , Semivida , Ácidos Indolacéticos/química , Ácidos Indolacéticos/farmacocinética , Indometacina/análogos & derivados , Indometacina/química , Indometacina/farmacocinética , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Ratas , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , 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 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.
Asunto(s)
Antagonistas de Prostaglandina/química , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Animales , Células CHO , Cricetinae , Ratones , Antagonistas de Prostaglandina/metabolismo , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismoRESUMEN
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
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.