Discovery and Structural Modification of 1-Phenyl-3-(1-phenylethyl)urea Derivatives as Inhibitors of Complement

• 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, 7I, and 7o) greatly improving their activity. Optimized compound 7I has an excellent inhibition activity with IC50 values as low as 13 nM. We demonstrated that the compound 7I inhibited C9 deposition through the classical, the lectin, and the alternative pathways but had no influence on C3 and C4 depositions.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medicinal Chemistry (hsv//eng)

Keyword

high-throughput screening

structural modification

complement

inhibitors

C9

Publication and Content Type

art (subject category)

ref (subject category)