Discovery And Optimization Of Selective Inhibitors Of Meprin Alpha (Part Ii)

Meprin alpha is a zinc metalloproteinase (metzincin) that has been implicated in multiple diseases, including fibrosis and cancers. It has proven difficult to find small molecules that are capable of selectively inhibiting meprin alpha, or its close relative meprin beta, over numerous other metzincins which, if inhibited, would elicit unwanted effects. We recently identified possible molecular starting points for meprin alpha-specific inhibition through an HTS effort (see part I, preceding paper). Here, in part II, we report further efforts to optimize potency and selectivity. We hope that a hydroxamic acid meprin alpha inhibitor probe will help define the therapeutic potential for small molecule meprin alpha inhibition and spur further drug discovery efforts in the area of zinc metalloproteinase inhibition.