Platelet activation has been reported to play a major role in arterial
thrombosis,
cancer metastasis, and progression. Recently, we developed a novel Ir(III)-based compound, [Ir(Cp∗)1-(2-pyridyl)-3-(4-dimethylaminophenyl)imidazo[1,5-a]
pyridine Cl]BF4 or Ir-6 and assessed its effectiveness as an
antiplatelet drug. Ir-6 exhibited higher potency against human platelet aggregation stimulated by
collagen. Ir-6 also inhibited
ATP-release, intracellular Ca2+ mobilization,
P-selectin expression, and the phosphorylation of
phospholipase Cγ2 (PLCγ2),
protein kinase C (PKC), v-Akt murine
thymoma viral oncogene (Akt)/
protein kinase B, and
mitogen-activated protein kinases (MAPKs), in
collagen-activated platelets. Neither the
adenylate cyclase inhibitor SQ22536 nor the
guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one significantly reversed the Ir-6-mediated inhibition of
collagen-induced platelet aggregation. Moreover, Ir-6 did not considerably diminish
OH radical signals in
collagen-activated platelets or Fenton reaction
solution. At 2 mg/kg, Ir-6 markedly prolonged the bleeding time in experimental mice. In conclusion, Ir-6 plays a crucial role by inhibiting platelet activation through the inhibition of signaling pathways, such as the PLCγ2-PKC cascade and the subsequent suppression of Akt and MAPK activation, thereby ultimately inhibiting platelet aggregation. Therefore, Ir-6 is a potential therapeutic agent for preventing or treating thromboembolic disorders or disrupting the interplay between platelets and
tumor cells, which contributes to
tumor cell growth and progression.