RESUMO
A novel GPR119 agonist based on the 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole scaffold was designed through lead optimization starting from pyrazole-based GPR119 agonist 1. The design is centered on the conformational restriction of the core scaffold, while minimizing the change in spatial relationships of two key pharmacophoric elements (piperidine-carbamate and aryl sulfone).
Assuntos
Pirazóis/química , Receptores Acoplados a Proteínas G/agonistas , Carbamatos/química , Humanos , Piperidinas/química , Ligação Proteica , Pirazóis/síntese química , Pirazóis/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-AtividadeRESUMO
The discovery of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor is described. The characterization and redressing of the issues associated with these compounds is detailed. An efficient three-step synthesis and a binding assay were relied upon as the primary means of rapidly improving potency and ADMET properties for this class of inverse agonist compounds. Compound 10 n bearing distributed polarity in the form of an imidazo-thiazole acetamide and a phenyl triazole is a unit lower in logP and has significantly improved binding affinity compared to the hit molecule 10a, providing support for further optimization of this series of compounds.
Assuntos
Azetidinas/química , Piperidinas/química , Receptores de Grelina/agonistas , Animais , Azetidinas/síntese química , Azetidinas/farmacocinética , Agonismo Inverso de Drogas , Humanos , Microssomos Hepáticos/metabolismo , Ratos , Receptores de Grelina/metabolismo , Relação Estrutura-AtividadeRESUMO
Cyclohexylglycine amides of various fluorinated pyrrolidines and azetidines were prepared and tested for activity against dipeptidyl peptidase IV and in vivo in the KK mouse model of type 2 diabetes. The tetrafluoropyrrolidide, cis-3,4-difluoropyrrolidide and the fluorinated azetidides displayed unexpectedly strong activity.
