LPA ₁ receptor

AM095 is a potent LPA ₁ receptor antagonist because it inhibits GTPγS binding to Chinese hamster ovary (CHO) cell membranes overexpressing recombinant human or mouse LPA ₁ with IC ₅₀ values of 0.98 and 0.73 μM, respectively. AM095 inhibits LPA-driven chemotaxis of CHO cells overexpressing mouse LPA ₁ (IC ₅₀ =778 nM) and human A2058 melanoma cells (IC ₅₀ =233 nM). The IC ₅₀ of AM095 in the human LPA ₁ GTPγS binding assay is comparable with that of our previously published compound AM966 (IC ₅₀ =0.98±0.17 μM) and the Debio-0719 compound (IC ₅₀ =0.60±0.04 μM). AM095 inhibits the LPA-induced calcium flux of CHO cells stably transfected with human or mouse LPA ₁ . The IC ₅₀ for AM095 antagonism of LPA-induced calcium flux of human or mouse LPA ₁ -transfected CHO cells is 0.025 and 0.023 μM, respectively.

AM095 has high oral bioavailability and a moderate half-life and is well tolerated at the doses tested in rats and dogs after oral and intravenous dosing. After oral (10 mg/kg) dosing in rats, AM095 plasma concentrations peaked at 2 h with a C _max of 41 μM, thereafter decreasing to 10 nM by 24 h. After intravenous (2 mg/kg) dosing, a C _max of 12 μM is observed within 15 min, which also decreased to approximately 10 nM by 24 h, yielding a t _1/2 of 1.79 h. In dogs, a single oral dose of 5 mg/kg yielded a peak plasma concentration of 21 μM within 15 min of dosing, which then decreased to 10 nM by 24 h. In contrast, an intravenous dose of 2 mg/kg resulted in a C _max of 11 μM within 15 min and decreased to 15 nM by 8 h, yielding a t _1/2 of 1.5 h.