RESUMO
The G protein-coupled P2Y2 receptor, activated by ATP and UTP has been reported as a potential drug target for a wide range of important clinical conditions, such as tumor metastasis, kidney disorders, and in the treatment of inflammatory conditions. However, pharmacological studies on this receptor have been impeded by the limited reported availability of stable, potent and selective P2Y2R antagonists. This article describes the design and synthesis of AR-C118925, a potent and selective non-nucleotide antagonist of the P2Y2 receptor discovered using the endogenous P2Y2R agonist UTP as the chemical starting point.
Assuntos
Dibenzocicloeptenos/síntese química , Antagonistas do Receptor Purinérgico P2Y/síntese química , Pirimidinonas/síntese química , Receptores Purinérgicos P2Y2/metabolismo , Uridina Trifosfato/química , Dibenzocicloeptenos/química , Dibenzocicloeptenos/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligação Proteica , Antagonistas do Receptor Purinérgico P2Y/química , Antagonistas do Receptor Purinérgico P2Y/metabolismo , Pirimidinonas/química , Pirimidinonas/metabolismo , Receptores Purinérgicos P2Y2/química , Uridina Trifosfato/metabolismoRESUMO
The CXCR2 SAR of a series of bicyclic antagonists such as the 2-aminothiazolo[4,5-d]pyrimidine 3b was investigated by systematic variation of the fused pyrimidine-based heterocyclic cores. Replacement of the aminothiazole ring with a 2-thiazolone alternative led to a series of thiazolo[4,5-d]pyrimidine-2(3H)-one antagonists with markedly improved biological and pharmacokinetic properties, which are suitable pharmacological tools to probe the in vivo effects of CXCR2 antagonism combined with the associated CCR2 activity.