title: A novel series of arylsulfonylthiophene-2-carboxamidine inhibitors of the complement component C1s.
abstract: 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.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 665 Stockton Drive, Exton, PA 19341, USA. nsubasin@prdus.jnj.com
authors.forename: Nalin L
authors.initials: NL
authors.lastname: Subasinghe
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Travins
authors.forename: Farah
authors.initials: F
authors.lastname: Ali
authors.forename: Hui
authors.initials: H
authors.lastname: Huang
authors.forename: Shelley K
authors.initials: SK
authors.lastname: Ballentine
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Marugán
authors.forename: Ehab
authors.initials: E
authors.lastname: Khalil
authors.forename: Heather R
authors.initials: HR
authors.lastname: Hufnagel
authors.forename: Roger F
authors.initials: RF
authors.lastname: Bone
authors.forename: Renee L
authors.initials: RL
authors.lastname: DesJarlais
authors.forename: Carl S
authors.initials: CS
authors.lastname: Crysler
authors.forename: Nisha
authors.initials: N
authors.lastname: Ninan
authors.forename: Maxwell D
authors.initials: MD
authors.lastname: Cummings
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Molloy
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Tomczuk
mesh_terms: 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
chemical_list: 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