RESUMEN

A number of pyrazolopyrimidines were synthesized and tested for their positive allosteric modulation of the HCA(2) receptor (GPR109A). Compound 24, an efficacious and potent agonist and allosteric enhancer of nicotinic acid's action, was the basis for most other compounds. Interestingly, some of the compounds were found to increase the efficacy of the endogenous ligand 3-hydroxybutyrate and enhance its potency almost 10-fold. This suggests that the pyrazolopyrimidines may have therapeutic value when given alone.

Asunto(s)

Pirazoles/síntesis química , Pirimidinas/síntesis química , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/metabolismo , Ácido 3-Hidroxibutírico/metabolismo , Regulación Alostérica , Sinergismo Farmacológico , Guanosina 5'-O-(3-Tiotrifosfato)/farmacología , Células HEK293 , Humanos , Niacina/farmacología , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Ensayo de Unión Radioligante , Receptores Acoplados a Proteínas G/agonistas , Relación Estructura-Actividad