RESUMO
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.
Assuntos
Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Piperazinas/síntese química , Piperazinas/farmacologia , Receptores LHRH/antagonistas & inibidores , Animais , Disponibilidade Biológica , Células Cultivadas , Meia-Vida , Compostos Heterocíclicos/farmacocinética , Humanos , Masculino , Piperazinas/farmacocinética , Ratos , Ratos Sprague-DawleyRESUMO
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.
Assuntos
Imidazóis/química , Pirimidinas/química , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Desenvolvimento Ósseo/efeitos dos fármacos , Linhagem Celular Tumoral , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Imidazóis/síntese química , Imidazóis/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pirimidinas/síntese química , Pirimidinas/farmacologia , Proteínas Recombinantes de Fusão/agonistas , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais , Crânio/metabolismo , Proteínas Wnt/agonistas , Proteínas Wnt/genética , Proteína Wnt3 , Proteína Wnt3A , beta Catenina/agonistasRESUMO
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.
Assuntos
Osteogênese/efeitos dos fármacos , Piperidinas/farmacologia , Pirimidinas/farmacologia , Proteínas Wnt/agonistas , beta Catenina/agonistas , Animais , Domínio Catalítico , Linhagem Celular Tumoral , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/química , Glicogênio Sintase Quinase 3 beta , Humanos , Camundongos , Modelos Moleculares , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Ratos , Transdução de Sinais/efeitos dos fármacos , Proteínas Wnt/metabolismo , beta Catenina/metabolismoRESUMO
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.
Assuntos
Benzimidazóis/síntese química , Quinoxalinas/síntese química , Receptores LHRH/antagonistas & inibidores , Administração Oral , Animais , Benzimidazóis/química , Benzimidazóis/farmacologia , Ligação Competitiva , Disponibilidade Biológica , Meia-Vida , Humanos , Técnicas In Vitro , Hormônio Luteinizante/sangue , Masculino , Microssomos Hepáticos/metabolismo , Orquiectomia , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Quinoxalinas/química , Quinoxalinas/farmacologia , Ensaio Radioligante , Ratos , Relação Estrutura-AtividadeRESUMO
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.
