RESUMEN
Gamma-lactam analogs (2) of EP(4) receptor agonists were identified by substitution of the pyrazolidinone ring (1) with a pyrrolidinone ring. Several compounds (such as 2a, 2h) with high potency, selectivity and acceptable PK profiles were discovered. These were assessed in animal models of ovulation induction and bronchoconstriction.
Asunto(s)
Lactamas/síntesis química , Lactamas/farmacología , Receptores de Prostaglandina E/agonistas , Animales , Femenino , Cobayas , Humanos , Lactamas/farmacocinética , Masculino , Ratones , Inducción de la Ovulación , Subtipo EP2 de Receptores de Prostaglandina E , Subtipo EP4 de Receptores de Prostaglandina E , Relación Estructura-ActividadRESUMEN
Replacement of the hydroxy cyclopentanone ring in PGE(2) with chemically more stable heterocyclic rings and substitution of the unsaturated alpha-alkenyl chain with a metabolically more stable phenethyl chain led to the development of potent and selective analogs of PGE(2). Compound 10f showed the highest potency and selectivity for EP(4) the receptor.
Asunto(s)
Dinoprostona/síntesis química , Pirazoles/síntesis química , Receptores de Prostaglandina E/agonistas , Animales , Dinoprostona/farmacología , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Ratones , Pirazoles/farmacología , Ratas , Receptores de Prostaglandina E/fisiología , Subtipo EP2 de Receptores de Prostaglandina E , Subtipo EP4 de Receptores de Prostaglandina ERESUMEN
In the course of a high throughput screening, a series of pyrazole compounds were identified with luteinizing hormone receptor (LH-R) agonist activity. A focused pyrazole library was produced by solid-phase synthesis and key pyrazole regioisomers were obtained selectively in solution. Evaluation of those compounds in a cAMP assay in CHO cells transfected with h-LH receptor allowed us to propose a structure-activity relationship model for this series and led to the identification of the first low molecular weight molecule with in vitro activity in a Leydig cells assay (ED(50)=1.31 microM) and in vivo in a model of testosterone induction in rats (significant effect at 32 mpk ip).