Article

A novel series of arylsulfonylthiophene-2-carboxamidine inhibitors of the complement component C1s.

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 665 Stockton Drive, Exton, PA 19341, USA.
Bioorganic & Medicinal Chemistry Letters (impact factor: 2.55). 04/2006; 16(8):2200-4. DOI:10.1016/j.bmcl.2006.01.036 pp.2200-4
Source: PubMed

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.

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Keywords

>1000-fold selectivity
 
activation
 
acute transplant rejection
 
C1s inhibitory activity
 
disease states
 
hereditary angioedema
 
potent compound
 
serine protease C1s
 
therapeutic intervention
 
thrombin