RESUMO
A novel series of 1,2,4-triazolyl 5-azaspiro[2.4]heptanes with high affinity and selectivity at the dopamine (DA) D3 receptor (D3R) is described. Some of these compounds also have high selectivity over the hERG channel and were characterized with respect to their pharmacokinetic properties both in vitro and in vivo during lead identification and early lead optimization phases. A few derivatives with overall favorable developability characteristics were selected for further late lead optimization studies.
Assuntos
Heptanos/química , Heptanos/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Animais , Células CHO , Cricetulus , Cristalografia por Raios X , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Modelos Moleculares , Receptores de Dopamina D3/metabolismo , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologiaRESUMO
A novel series of 1,2,4-triazolyl octahydropyrrolo[2,3-b]pyrroles showing high affinity and selectivity at the DA D3 receptor is reported here. Compounds endowed with high selectivity over the hERG channel were identified and their pharmacokinetic properties thoroughly analyzed. A few derivatives with appropriate developability characteristics were selected for further studies and progression along the screening cascade. In particular, derivative 60a, (DA D3 pKi=8.4, DA D2 pKi=6.0 and hERG fpKi=5.2) showed a balanced profile and further refinements are in progress around this molecule.
Assuntos
Pirróis/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Triazóis/farmacologia , Animais , Ligação Competitiva/efeitos dos fármacos , Células CHO , Cricetulus , Relação Dose-Resposta a Droga , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Células HEK293 , Humanos , Modelos Moleculares , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/químicaRESUMO
A new series of morpholine derivatives has been identified as selective DA D3 receptor antagonists; their in vitro profile and pharmacokinetic data are provided.
Assuntos
Antagonistas dos Receptores de Dopamina D2/química , Morfolinas/química , Receptores de Dopamina D3/antagonistas & inibidores , Animais , Sítios de Ligação , Antagonistas dos Receptores de Dopamina D2/síntese química , Antagonistas dos Receptores de Dopamina D2/farmacocinética , Meia-Vida , Simulação de Acoplamento Molecular , Morfolinas/síntese química , Morfolinas/farmacocinética , Estrutura Terciária de Proteína , Ratos , Receptores de Dopamina D3/metabolismoRESUMO
A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes with high affinity and selectivity for the DA D(3) receptor and excellent pharmacokinetic profiles was recently reported. We also recently discussed the role of the linker associated with the triazole moiety. In this manuscript, we are reporting a detailed exploration of the region of the receptor interacting with the amine terminus of the scaffold wherein SAR and developability data associated with these novel templates was undertaken.
Assuntos
Compostos Azabicíclicos/síntese química , Modelos Moleculares , Receptores de Dopamina D3/antagonistas & inibidores , Triazóis/síntese química , Animais , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Células CHO , Domínio Catalítico , Cricetinae , Cricetulus , Humanos , Técnicas In Vitro , Microssomos Hepáticos/metabolismo , Ensaio Radioligante , Ratos , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologiaRESUMO
Novel series of pyrrole-pyrazinone and pyrazole-pyrazinone have been identified as potent and selective Vasopressin(1b) receptor antagonists. Exploration of the substitution pattern around the core of these templates allowed generation of compounds with high inhibitory potency at the Vasopressin(1b) receptor, including examples that showed good selectivity with respect to Vasopressin(1a), Vasopressin(2), and Oxytocin receptor subtypes.
