Design, Synthesis, and Antitumor Activity Evaluation of Novel Dual A2A/A2B Adenosine Receptor Antagonists.
TL;DR
The development of compound 45 is reported, a novel imidazopyrazine derivative acting as a long-lasting, dual A2A/A2B receptor antagonist with nanomolar in vitro potency, providing high oral bioavailability and systemic exposure across multiple preclinical species.
Abstract
Adenosine is an essential signaling molecule with a well-recognized role in the central nervous, cardiovascular, and immune systems. Its immunosuppressive effects have gained significant attention in oncology, as adenosine accumulation within the tumor microenvironment can profoundly inhibit antitumor immunity. Therapeutic strategies to counteract this pathway include inhibiting adenosine-generating enzymes CD39 and CD73 or blocking adenosine A2A and A2B receptors. In this study, we report the development of compound 45, a novel imidazopyrazine derivative acting as a long-lasting, dual A2A/A2B receptor antagonist with nanomolar in vitro potency. This compound exhibits extended receptor residence time and maintains dual antagonistic activity even at high micromolar adenosine levels. Compound 45 demonstrates favorable ADME characteristics as well as pharmacokinetic properties, providing high oral bioavailability and systemic exposure across multiple preclinical species. In efficacy studies, this agent robustly reduced metastatic burden in a murine MCA205 pulmonary metastasis model.