RESUMEN
As part of a program aimed at the discovery of antinociceptive therapy for inflammatory conditions, a screening hit was found to inhibit microsomal prostaglandin E synthase-1 (mPGES-1) with an IC50 of 17.4 µM. Structural information was used to improve enzyme potency by over 1000-fold. Addition of an appropriate substituent alleviated time-dependent cytochrome P450 3A4 (CYP3A4) inhibition. Further structure-activity relationship (SAR) studies led to 8, which had desirable potency (IC50 = 12 nM in an ex vivo human whole blood (HWB) assay) and absorption, distribution, metabolism, and excretion (ADME) properties. Studies on the formulation of 8 identified 8·H3PO4 as suitable for clinical development. Omission of a lipophilic portion of the compound led to 26, a readily orally bioavailable inhibitor with potency in HWB comparable to celecoxib. Furthermore, 26 was selective for mPGES-1 inhibition versus other mechanisms in the prostanoid pathway. These factors led to the selection of 26 as a second clinical candidate.
Asunto(s)
Analgésicos/síntesis química , Analgésicos/farmacología , Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/farmacología , Imidazoles/síntesis química , Imidazoles/farmacología , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Microsomas/enzimología , Animales , Antiinflamatorios no Esteroideos/farmacología , Disponibilidad Biológica , Celecoxib/farmacología , Inhibidores de la Ciclooxigenasa/farmacocinética , Citocromo P-450 CYP3A , Inhibidores Enzimáticos del Citocromo P-450/síntesis química , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Perros , Descubrimiento de Drogas , Humanos , Microsomas/efectos de los fármacos , Modelos Moleculares , Prostaglandina-E Sintasas , Ratas , Relación Estructura-ActividadRESUMEN
Novel arylthiomethyl morpholines are potent selective norepinephrine reuptake inhibitors (NERIs) and dual serotonin/norepinephrine reuptake inhibitors (SRI/NERIs). The target compounds were prepared using a stereochemically versatile synthesis featuring an aldol condensation as the key step. One enantiomer of the 2-methoxy-substituted analogue was found to be a potent and selective norepinephrine reuptake inhibitor, whereas the opposite enantiomer was a potent dual serotonin/norepinephrine reuptake inhibitor.
Asunto(s)
Inhibidores de Captación Adrenérgica/síntesis química , Morfolinas/síntesis química , Norepinefrina/antagonistas & inhibidores , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores de Captación Adrenérgica/farmacología , Aminas Biogénicas/antagonistas & inhibidores , Aminas Biogénicas/metabolismo , Humanos , Morfolinas/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Tin-lithium exchange allows the formation of alpha-amino-organolithium species that undergo anionic cyclization onto allylic ethers to give 3-alkenylpyrrolidines. The methodology has been applied to the synthesis of an advanced intermediate related to the natural product (-)-alpha-kainic acid.
