A novel series of arylsulfonylthiophene-2-carboxamidine inhibitors of the complement component C1s.
Inhibiting the classical pathway of complement activation by attenuating the proteolytic activity of the serine protease C1s is a potential strategy for the therapeutic intervention in disease states such as hereditary angioedema, ischemia-reperfusion injury, and acute transplant rejection. A series of arylsulfonylthiophene-2-carboxamidine inhibitors of C1s were synthesized and evaluated for C1s inhibitory activity. The most potent compound had a Ki of 10nM and >1000-fold selectivity over uPA, tPA, FX(a), thrombin, and plasmin.
Subasinghe
Nalin L
NL
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 665 Stockton Drive, Exton, PA 19341, USA. nsubasin@prdus.jnj.com
Travins
Jeremy M
JM
Ali
Farah
F
Huang
Hui
H
Ballentine
Shelley K
SK
Marugán
Juan José
JJ
Khalil
Ehab
E
Hufnagel
Heather R
HR
Bone
Roger F
RF
DesJarlais
Renee L
RL
Crysler
Carl S
CS
Ninan
Nisha
N
Cummings
Maxwell D
MD
Molloy
Christopher J
CJ
Tomczuk
Bruce E
BE
D000578:Amidines / Q000138:chemical synthesis / Q000494:pharmacology; D000799:Angioedema / Q000188:drug therapy; D001190:Arylsulfonates / Q000138:chemical synthesis* / Q000494:pharmacology; D003173:Complement C1s / Q000037:antagonists & inhibitors*; D005341:Fibrinolysin / Q000494:pharmacology; D006084:Graft Rejection / Q000188:drug therapy; D006801:Humans; D017202:Myocardial Ischemia / Q000188:drug therapy; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology
D000578:Amidines; D001190:Arylsulfonates; D015842:Serine Proteinase Inhibitors; D013876:Thiophenes; D003173:Complement C1s; D013917:Thrombin; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; D013755:Tetradecanoylphorbol Acetate