The complement system is one of the major defense mechanisms of the innate immune system composed of the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP). There is strong scientific evidence for AP involvement in diseases such as age-related macular degeneration (AMD) or paroxysmal nocturnal hemoglobinuria (PNH). We report on the discovery and preclinical evaluation of highly potent and selective low-molecular weight alternative pathway inhibitors which were identified using structure guided optimization.