RESUMEN
ENPP1 acts as a negative regulator of the cGAS-STING pathway through the hydrolysis of 2'3'-cGAMP. Inhibitors of ENPP1 are regarded as promising agents for stimulating the immune response in cancer immunotherapy. This study describes the identification and optimization of imidazo[1,2-a]pyrazine derivative 7 as a highly potent and selective ENPP1 inhibitor. Compound 7 demonstrated substantial inhibitory activity against ENPP1 with an IC50 value of 5.70 or 9.68 nM while showing weak inhibition against ENPP2 and ENPP3. Furthermore, compound 7 was shown to enhance the mRNA expression of cGAMP-induced STING pathway downstream target genes, such as IFNB1, CXCL10, and IL6. In vivo pharmacokinetic and antitumor studies showed promising results, with 7 not only exhibiting efficient pharmacokinetic properties but also enhancing the antitumor efficacy of the anti-PD-1 antibody. Treatment with 7 (80 mg/kg) combined with anti-PD-1 antibody achieved a tumor growth inhibition rate of 77.7% and improved survival in a murine model.
Asunto(s)
Antineoplásicos , Hidrolasas Diéster Fosfóricas , Pirazinas , Pirofosfatasas , Pirazinas/farmacología , Pirazinas/química , Pirazinas/síntesis química , Pirazinas/farmacocinética , Pirazinas/uso terapéutico , Animales , Hidrolasas Diéster Fosfóricas/metabolismo , Humanos , Pirofosfatasas/antagonistas & inhibidores , Pirofosfatasas/metabolismo , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Relación Estructura-Actividad , Imidazoles/farmacología , Imidazoles/química , Imidazoles/síntesis química , Imidazoles/farmacocinética , Descubrimiento de Drogas , Línea Celular Tumoral , Masculino , Inhibidores de Fosfodiesterasa/farmacología , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacocinética , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/uso terapéutico , Femenino , RatasRESUMEN
A novel protocol for Rh(iii)-catalyzed switchable C-H acylmethylation and annulation of 2,2'-bipyridine derivatives with sulfoxonium ylides is reported. This protocol provides a facile approach to synthesize structurally diverse acylmethylated 2,2'-bipyridine derivatives and acyl pyrido[2,3-a]indolizines with a broad range of functional group tolerance.
