AM966

AM966 is a potent, selective and orally active LPA (1) receptor antagonist which inhibits lung fibrosis in the mouse bleomycin model.Last. In vitro, AM966 inhibited LPA-stimulated intracellular calcium release (IC (50) = 17 nM) from Chinese hamster ovary cells stably expressing human LPA (1) receptors and inhibited LPA-induced chemotaxis (IC (50) = 181 nM) of human IMR-90 lung fibroblasts expressing LPA (1) receptors. AM966 demonstrated a good pharmacokinetic profile following oral dosing in mice. In the mouse, AM966 reduced lung injury, vascular leakage, inflammation and fibrosis at multiple time points following intratracheal bleomycin instillation. AM966 also decreased lactate dehydrogenase activity and tissue inhibitor of metalloproteinase-1, transforming growth factor beta1, hyaluronan and matrix metalloproteinase-7, in bronchoalveolar lavage fluid.