AM966

AM966 is a high affinity, selective, oral LPA₁-antagonist, inhibits LPA-stimulated intracellular calcium release (IC₅₀=17 nM). IC50 & Target:LPA₁^[1] In Vitro:AM966 is a potent, selective, orally bioavailable LPA₁ receptor antagonist. AM966 inhibits LPA₁-mediated chemotaxis of human A2058 melanoma cells (IC₅₀=138±43 nM), IMR-90 human lung fibroblasts (IC₅₀=182±86 nM) and CHO mLPA₁ cells (IC₅₀=469±54 nM)^[1]. LPA-induced ERK1/2 activation is completely blocked by AM966 (100 nM), which selectively antagonizes LPA₁ over LPA_2-5, with an IC₅₀ value of 3.8±0.4 nM. Pre-treatment with AM966 (100 nM) completely blocks ERK1/2 phosphorylation induced by Mianserin^[2]. In Vivo:AM966 (30 mg/kg, BID) reduces vascular leakage, inflammation and lung injury and inflammation in a 3 day bleomycin model. AM966 inhibits lung fibrosis, maintains mouse body weight and decreases lung inflammation 14 days after bleomycin lung injury. AM966 reduces vascular leakage, tissue injury and pro-fibrotic cytokine production in the 14 day bleomycin study. AM966 demonstrates greater efficacy compared to pirfenidone in the 14 day bleomycin model. AM966 decreases mortality and fibrosis at late time points after bleomycin injury^[1].