Small molecule inhibitors of mannan-binding lectin-associated serine Proteases-2 and-3

The complement system of innate immunity recognizes, opsonizes, and kills invading pathogens and damaged cells, and stimulates an inflammatory response. Inappropriate or excessive complement activity is associated with a wide variety of pathological conditions, and several drugs targeting complement components have been approved. Here we describe the discovery and structure-activity relationships of a novel class of 2-aminoimidazole-containing inhibitors of mannan-binding lectin-associated serine proteases -2 and -3 (MASP-2 and MASP-3), essential enzymes for activation of the lectin and alternative pathways of complement, respectively. With a high degree of target selectivity and favorable in vitro pharmacological properties, this inhibitor series has the potential to be developed as treatments for numerous diseases and pathological conditions.