RESUMEN
Antagonism of the gonadotropin releasing hormone (GnRH) receptor has resulted in positive clinical results in reproductive tissue disorders such as endometriosis and prostate cancer. Following the recent discovery of orally active GnRH antagonists based on a 4-piperazinylbenzimidazole template, we sought to investigate the properties of heterocyclic isosteres of the benzimidazole template. We report here the synthesis and biological activity of eight novel scaffolds, including imidazopyridines, benzothiazoles and benzoxazoles. The 2-(4-tert-butylphenyl)-8-(piperazin-1-yl)imidazo[1,2-a]pyridine ring system was shown to have nanomolar binding potency at the human and rat GnRH receptors as well as functional antagonism in vitro. Additional structure-activity relationships within this series are reported along with a pharmacokinetic comparison to the benzimidazole-based lead molecule.
Asunto(s)
Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Piperazinas/síntesis química , Piperazinas/farmacología , Receptores LHRH/antagonistas & inhibidores , Animales , Disponibilidad Biológica , Células Cultivadas , Semivida , Compuestos Heterocíclicos/farmacocinética , Humanos , Masculino , Piperazinas/farmacocinética , Ratas , Ratas Sprague-DawleyRESUMEN
A series of (hetero)arylpyrimidines agonists of the Wnt-beta-catenin cellular messaging system have been prepared. These compounds show activity in U2OS cells transfected with Wnt-3a, TCF-luciferase, Dkk-1 and tk-Renilla. Selected compounds show minimal GSK-3beta inhibition indicating that the Wnt-beta-catenin agonism activity most likely comes from interaction at Wnt-3a/Dkk-1. Two examples 1 and 25 show in vivo osteogenic activity in a mouse calvaria model. One example 1 is shown to activate non-phosphorylated beta-catenin formation in bone.
Asunto(s)
Imidazoles/química , Pirimidinas/química , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animales , Desarrollo Óseo/efectos de los fármacos , Línea Celular Tumoral , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Humanos , Imidazoles/síntesis química , Imidazoles/farmacología , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Ratones , Ratones Endogámicos C57BL , Pirimidinas/síntesis química , Pirimidinas/farmacología , Proteínas Recombinantes de Fusión/agonistas , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Transducción de Señal , Cráneo/metabolismo , Proteínas Wnt/agonistas , Proteínas Wnt/genética , Proteína Wnt3 , Proteína Wnt3A , beta Catenina/agonistasRESUMEN
A high-throughput screening campaign to discover small molecule leads for the treatment of bone disorders concluded with the discovery of a compound with a 2-aminopyrimidine template that targeted the Wnt beta-catenin cellular messaging system. Hit-to-lead in vitro optimization for target activity and molecular properties led to the discovery of (1-(4-(naphthalen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine (5, WAY-262611). Compound 5 has excellent pharmacokinetic properties and showed a dose dependent increase in the trabecular bone formation rate in ovariectomized rats following oral administration.
Asunto(s)
Osteogénesis/efectos de los fármacos , Piperidinas/farmacología , Pirimidinas/farmacología , Proteínas Wnt/agonistas , beta Catenina/agonistas , Animales , Dominio Catalítico , Línea Celular Tumoral , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/química , Glucógeno Sintasa Quinasa 3 beta , Humanos , Ratones , Modelos Moleculares , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Ratas , Transducción de Señal/efectos de los fármacos , Proteínas Wnt/metabolismo , beta Catenina/metabolismoRESUMEN
A previous report described the serum LH suppression pharmacology of the 2-phenyl-4-piperazinyl-benzimidazole N-ethyluracil GnRH receptor antagonist 1 following oral administration in rats. A series of small heterocycles were appended to the 2-(4-tert-butylphenyl)-4-piperazinyl-benzimidazole template in place of the N-ethyluracil. Two imidazole analogues, 32 and 41, were shown to possess substantial in vitro potency at the target receptor (hGnRH IC(50) = 7 and 18 nM, respectively) and aqueous solubility (55 and 100 microg/mL at pH 7.4, respectively). Both compounds had high oral bioavailability in rats and 32 was further examined in an orchidectomized rat model for serum LH suppression based on increased volume of distribution over 41. Serum LH levels trended lower in orchidectomized rats following oral administration of 32.
Asunto(s)
Bencimidazoles/farmacología , Piperazinas/farmacología , Receptores LHRH/antagonistas & inhibidores , Administración Oral , Animales , Bencimidazoles/química , Bencimidazoles/farmacocinética , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Hormona Luteinizante/sangre , Modelos Animales , Piperazinas/química , Piperazinas/farmacocinética , Ratas , Receptores LHRH/metabolismo , Relación Estructura-Actividad , Factores de TiempoRESUMEN
A potent, highly insoluble, GnRH antagonist with a 2-phenyl-4-piperazinylbenzimidazole template and a quinoxaline-2,3-dione pharmacophore was modified to maintain GnRH antagonist activity and improve in vitro pharmaceutical properties. Structural changes to the quinoxaline-2,3-dione portion of the molecule resulted in several structures with improved properties and culminated in the discovery of 6-([4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl] methyl)quinoxaline (WAY-207024). The compound was shown to have excellent pharmacokinetic parameters and lowered rat plasma LH levels after oral administration.