A2AR-antagonist-1 (compound 38), an orally active adenosine A2A receptor antagonist with an IC50 value of 29 nM, demonstrates anti-tumor properties and stability in mouse liver microsomes (t1/2 = 86.1 min). Additionally, it activates T cells by inhibiting immunosuppressive molecules (LAG-3 and TIM-3) and promoting expression of effector molecules (GZMB, IFNG, and IL-2) [1].

A2AR:29 nM

A2AR-antagonist-1 (0.001-10 μM; 30 minutes) reduces NECA-induced phosphorylation of ERK levels in HEK293-A2AR cells [1]. At concentrations of 0.1-10 μM over 5 hours, this compound inhibits NECA-induced expression of immune molecules and increases the expression of effector molecules in Jurkat T cells (human immortalized T lymphocyte line) [1]. Furthermore, A2AR-antagonist-1 (0.1-10 μM; 48 hours) restores the impaired cytotoxic function of OT-I mouse splenocytes (OT-I CTL) against MC38-OVA cells and enhances in vitro T cell activation and effector functions [1].

A2AR-antagonist-1 (100 mg/kg; oral administration; once daily for 23 days) demonstrated remarkable antitumor activity in C57BL/6 mice carrying MC38 colon carcinoma cells [1]. Pharmacokinetic analysis in mice [1] revealed the following: Route Dose (mg/kg) C max (ng/mL) AUC 0-last (ng·h/mL) AUC 0-t (ng·h/mL) t 1/2 (h) F (%) for intravenous (i.v.) administration at 2 mg/kg resulted in a C max of 2584 ng/mL, AUC 0-last of 5577 ng·h/mL, AUC 0-t of 5565 ng·h/mL, and a half-life (t 1/2) of 0.93 h, while oral (p.o.) administration at 10 mg/kg achieved a C max of 8823 ng/mL, AUC 0-last of 24008 ng·h/mL, AUC 0-t of 24003 ng·h/mL, t 1/2 of 2.35 h, and bioavailability (F) of 86.1%.