A novel series of potent and selective small molecule inhibitors of the complement component C1s.
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.
Subasinghe
Nalin L
NL
3-Dimensional Pharmaceuticals Inc, 665 Stockton Drive, Exton, PA 19341, USA. nsubasin@prdus.jnj.com
Ali
Farah
F
Illig
Carl R
CR
Jonathan Rudolph
M
M
Klein
Scott
S
Khalil
Ehab
E
Soll
Richard M
RM
Bone
Roger F
RF
Spurlino
John C
JC
DesJarlais
Renee L
RL
Crysler
Carl S
CS
Cummings
Maxwell D
MD
Morris
Philip E
PE
Kilpatrick
John M
JM
Sudhakara Babu
Y
Y
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
D003172:Complement C1; D003169:Complement Inactivator Proteins; D011720:Pyrazoles; D015842:Serine Proteinase Inhibitors; D013844:Thiazoles; D013876:Thiophenes; D012697:Serine Endopeptidases