title: A novel series of potent and selective small molecule inhibitors of the complement component C1s.
abstract: Activation of the classical pathway of complement has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury and acute transplant rejection. The trypsin-like serine protease C1s represents a pivotal upstream point of control in the classical pathway of complement activation and is therefore likely to be a useful target in the therapeutic intervention of these disease states. A series of thiopheneamidine-based inhibitors of C1s has been optimized to give a 70 nM inhibitor that inhibits the classical pathway of complement activation in vitro.
authors.affiliation: 3-Dimensional Pharmaceuticals Inc, 665 Stockton Drive, Exton, PA 19341, USA. nsubasin@prdus.jnj.com
authors.forename: Nalin L
authors.initials: NL
authors.lastname: Subasinghe
authors.forename: Farah
authors.initials: F
authors.lastname: Ali
authors.forename: Carl R
authors.initials: CR
authors.lastname: Illig
authors.forename: M
authors.initials: M
authors.lastname: Jonathan Rudolph
authors.forename: Scott
authors.initials: S
authors.lastname: Klein
authors.forename: Ehab
authors.initials: E
authors.lastname: Khalil
authors.forename: Richard M
authors.initials: RM
authors.lastname: Soll
authors.forename: Roger F
authors.initials: RF
authors.lastname: Bone
authors.forename: John C
authors.initials: JC
authors.lastname: Spurlino
authors.forename: Renee L
authors.initials: RL
authors.lastname: DesJarlais
authors.forename: Carl S
authors.initials: CS
authors.lastname: Crysler
authors.forename: Maxwell D
authors.initials: MD
authors.lastname: Cummings
authors.forename: Philip E
authors.initials: PE
authors.lastname: Morris
authors.forename: John M
authors.initials: JM
authors.lastname: Kilpatrick
authors.forename: Y
authors.initials: Y
authors.lastname: Sudhakara Babu
mesh_terms: D001665:Binding Sites / Q000502:physiology; D003172:Complement C1 / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000138:chemical synthesis* / Q000494:pharmacology; D003171:Complement Pathway, Classical / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000201:enzymology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D003172:Complement C1; D003169:Complement Inactivator Proteins; D011720:Pyrazoles; D015842:Serine Proteinase Inhibitors; D013844:Thiazoles; D013876:Thiophenes; D012697:Serine Endopeptidases