RESUMEN
A series of 2-arylbenzimidazoles was synthesized and found to bind with high affinity to the human histamine H(4) receptor. Structure-activity relationships were investigated through library preparation and evaluation as well as traditional medicinal chemistry approaches, leading to the discovery of compounds with single-digit nanomolar affinity for the H(4) receptor.
Asunto(s)
Bencimidazoles/síntesis química , Bencimidazoles/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos/metabolismo , Aldehídos/química , Aminas/química , Bencimidazoles/química , Catálisis , Simulación por Computador , Histamina/metabolismo , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Unión Proteica , Receptores Acoplados a Proteínas G/química , Receptores Histamínicos/química , Receptores Histamínicos H4 , Relación Estructura-ActividadRESUMEN
A series of competitive, reversible cathepsin S (CatS) inhibitors was investigated. An earlier disclosure detailed the discovery of the 4-(2-keto-1-benzimidazolinyl)-piperidin-1-yl moiety as an effective replacement for the 4-arylpiperazin-1-yl group found in our screening hit. Continued investigation into replacements for the 4-aryl piperazine resulted in the identification of potentially useful CatS inhibitors with enzymatic and cellular activity similar to that of JNJ 10329670 as disclosed in a previous publication.
Asunto(s)
Compuestos Bicíclicos con Puentes/química , Catepsinas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Piperidinas/química , Animales , Sitios de Unión , Compuestos Bicíclicos con Puentes/farmacología , Línea Celular Tumoral , Inhibidores Enzimáticos/farmacología , Ratones , Piperidinas/farmacología , Relación Estructura-ActividadRESUMEN
A novel series of competitive, reversible cathepsin S (CatS) inhibitors was discovered and optimized. The 4-(2-keto-1-benzimidazolinyl)-piperidin-1-yl moiety was found to be an effective replacement for the 4-arylpiperazin-1-yl group found in our earlier series of CatS inhibitors. This replacement imparted improved PK properties as well as decreased off-target activity. Optimization of the ketobenzimidazole moiety led to the discovery of the lead compound JNJ 10329670, which represents a novel class of selective, noncovalent, reversible, and orally bioavailable inhibitors of cathepsin S.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Animales , Bencimidazoles/química , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Línea Celular , Compuestos Heterocíclicos con 2 Anillos/química , Compuestos Heterocíclicos con 2 Anillos/farmacología , Modelos Químicos , Estructura Molecular , Pirazoles/química , Pirazoles/farmacocinética , Pirazoles/farmacología , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacología , Relación Estructura-ActividadRESUMEN
The syntheses and biological activities of a novel series of 2,4- and 2,5-disubstituted thiophenes are reported. These analogues have shown excellent affinity and selectivity against alpha(1)-adrenoreceptor subtypes.
Asunto(s)
Hiperplasia Prostática/tratamiento farmacológico , Tiofenos/síntesis química , Tiofenos/farmacología , Antagonistas Adrenérgicos alfa/síntesis química , Antagonistas Adrenérgicos alfa/química , Antagonistas Adrenérgicos alfa/farmacología , Sitios de Unión , Humanos , Masculino , Estructura Molecular , Relación Estructura-Actividad , Tiofenos/químicaRESUMEN
Antagonists of the alpha(1)-adrenergic receptors (alpha(1)-ARs) are useful for the treatment of benign prostatic hyperplasia. A series of potent and subtype-selective alpha(1a)-AR antagonists has been synthesized, displaying in vitro binding affinity in the low the nanomolar range.