RESUMEN
We have identified naphthol derivatives as inhibitors of the vanilloid receptor TRPV1 by high throughput screening. The initial lead showed high clearance in rats and has been optimized by enhancing the acidity of the phenol group. Compound 6b has reduced clearance, improved potency and is active in rat cystometry models of urinary incontinence after intravenous administration.
Asunto(s)
Naftoles/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Incontinencia Urinaria/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Femenino , Concentración 50 Inhibidora , Estructura Molecular , Naftoles/síntesis química , Naftoles/uso terapéutico , Nutrición Parenteral , Ratas , Relación Estructura-ActividadRESUMEN
A new class of benzimidazole-5-sulfonamides has been identified as nonpeptide luteinizing hormone-releasing hormone (LHRH) antagonists. Initial structure-activity relationships are presented resulting in compounds 19 and 28 with submicromolar dual functional activity on human and rat receptors.
Asunto(s)
Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Animales , Humanos , Concentración 50 Inhibidora , Ligandos , Ratas , Relación Estructura-ActividadRESUMEN
The 2-cyclopropyl substituted benzimidazole 2 has been used as a starting point for further optimization of an LHRH antagonist series. SAR studies revealed that a tert-butyl urea fragment connected through a simple carbon chain would improve activity. Further modification of the benzylsulfonamide moiety led to the discovery of 23 (IC(50): 4.2 nM).