RESUMEN
As part of an on-going lead optimisation effort, a cross screening exercise identified an aryl sulphonyl amide hit that was optimised to afford a highly potent series of ghrelin receptor agonists.
Asunto(s)
Química Farmacéutica/métodos , Ghrelina/química , Receptores de Ghrelina/antagonistas & inhibidores , Sulfonas/química , Administración Oral , Animales , Disponibilidad Biológica , Diseño de Fármacos , Hormona del Crecimiento/química , Masculino , Modelos Químicos , Procesamiento Proteico-Postraduccional , Ratas , Ratas Sprague-Dawley , Receptores de Ghrelina/química , Relación Estructura-ActividadRESUMEN
A series of small molecule orally bioavailable ghrelin receptor agonists have been identified through systematic optimisation of a high throughput screening hit.
Asunto(s)
Indoles/farmacología , Receptores de Ghrelina/agonistas , Sulfonamidas/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Fluorescencia , Indoles/síntesis química , Masculino , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1B/metabolismo , Receptores de Ghrelina/metabolismo , Relación Estructura-Actividad , Sulfonamidas/síntesis químicaRESUMEN
Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating basic biaryl P4 groups, producing highly potent inhibitors with significant anticoagulant activities and encouraging oral pharmacokinetic profiles.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/química , Inhibidores del Factor Xa , Pirrolidinonas/química , Inhibidores de Serina Proteinasa/química , Animales , Anticoagulantes/química , Anticoagulantes/farmacocinética , Anticoagulantes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Interacciones Hidrofóbicas e Hidrofílicas , Masculino , Modelos Moleculares , Pirrolidinonas/farmacocinética , Pirrolidinonas/farmacología , Ratas , Ratas Sprague-Dawley , Inhibidores de Serina Proteinasa/farmacocinética , Inhibidores de Serina Proteinasa/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A silyl-modified variant of the Bellus-Claisen rearrangement is described; the generality of this rearrangement has been demonstrated with a range of allylic amines and ketenes.
Asunto(s)
Alquenos/química , Compuestos Alílicos/química , Aminas/química , Etilenos/química , Cetonas/química , Mesilatos/química , Modelos Químicos , Ciclización , Ésteres , Estructura Molecular , Estereoisomerismo , Compuestos de TrimetilsililoRESUMEN
A series of novel, non-basic 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group, was designed and synthesised. Within this series, the N-2-(morpholin-4-yl)-2-oxoethyl derivative 24 was shown to be a potent, selective fXa inhibitor with good anticoagulant activity. Moreover, 24 possessed highly encouraging rat and dog pharmacokinetic profiles with excellent oral bioavailabilities in both species.
Asunto(s)
Antitrombina III/farmacología , Fibrinolíticos/farmacología , Pirrolidinonas/farmacología , Trombina/efectos de los fármacos , Administración Oral , Animales , Antitrombina III/síntesis química , Disponibilidad Biológica , Fibrinolíticos/síntesis química , Masculino , Pirrolidinonas/síntesis química , Ratas , Ratas WistarRESUMEN
Structure-based drug design was exploited in the synthesis of 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group with acyclic tertiary amide termini. Optimized hydrophobic contacts of one amide substituent in P4 were complemented by hydrophobicity-modulating features in the second, producing potent fXa inhibitors including examples with excellent anticoagulant properties.