Discovery and StructuralModification of 1-Phenyl-3-(1-phenylethyl)urea Derivatives as Inhibitorsof Complement

摘要

A series of 1-phenyl-3-(1-phenylethyl)urea derivatives were identified as novel and potent complement inhibitors through structural modification of the original compound from high-throughput screening. Various analogues (>7 and >13–>15) were synthesized and identified as complement inhibitors, with the introduction of a five- or six-carbon chain (>7c, >7d, >7k, >7l, and >7o) greatly improving their activity. Optimized compound >7l has an excellent inhibition activity with IC50 values as low as 13 nM. We demonstrated that the compound >7l inhibited C9 deposition through the classical, the lectin, and the alternative pathways but had no influence on C3 and C4 depositions.