title: Discovery and Structural Modification of 1-Phenyl-3-(1-phenylethyl)urea Derivatives as Inhibitors of Complement.
abstract: 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.
authors.affiliation: Department of Chemistry and Institute of Medicinal Chemistry, East China Normal University , 3663 North Zhong Shan Road, Shanghai 200062, People's Republic of China ; Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, People's Republic of China.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China.
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Yang
authors.affiliation: Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Laboratory Medicine, Section of Medical Protein Chemistry, Lund University , S-205 02 Malmö, Sweden.
authors.forename: Tom W L
authors.initials: TW
authors.lastname: Groeneveld
authors.affiliation: Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China.
authors.forename: Pei-Lan
authors.initials: PL
authors.lastname: He
authors.affiliation: Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China.
authors.forename: Feng-Hua
authors.initials: FH
authors.lastname: Zhu
authors.affiliation: Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, People's Republic of China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Chemistry and Institute of Medicinal Chemistry, East China Normal University , 3663 North Zhong Shan Road, Shanghai 200062, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Laboratory Medicine, Section of Medical Protein Chemistry, Lund University , S-205 02 Malmö, Sweden.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blom
authors.affiliation: Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Zuo
authors.affiliation: Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, People's Republic of China.
authors.forename: Fa-Jun
authors.initials: FJ
authors.lastname: Nan
keywords: C9; complement inhibitors; high-throughput screening; structural modification