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.