1. A novel series of arylsulfonylthiophene-2-carboxamidine inhibitors of the complement component C1s
- Author
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Christopher J. Molloy, Nisha S. Ninan, Jeremy M. Travins, Hui Huang, Carl Crysler, Renee L. DesJarlais, Shelley K. Ballentine, Ehab Khalil, Juan J. Marugan, Farah Ali, Nalin L. Subasinghe, Bruce E. Tomczuk, Hufnagel Heather Rae, Maxwell D. Cummings, and Roger F. Bone
- Subjects
Graft Rejection ,Serine Proteinase Inhibitors ,Plasmin ,Clinical Biochemistry ,Amidines ,Myocardial Ischemia ,Pharmaceutical Science ,Thiophenes ,Pharmacology ,Biochemistry ,Classical complement pathway ,Complement inhibitor ,Structure-Activity Relationship ,Thrombin ,Drug Discovery ,medicine ,Humans ,Fibrinolysin ,Angioedema ,Arylsulfonates ,Molecular Biology ,Complement C1s ,Serine protease ,biology ,Chemistry ,Organic Chemistry ,Urokinase-Type Plasminogen Activator ,Complement system ,biology.protein ,Molecular Medicine ,Tetradecanoylphorbol Acetate ,medicine.drug - 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.
- Published
- 2005