Discovery and Optimization of Selective Inhibitors of Meprin α (Part II)

Abstract

Meprin α 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 α, or its close relative meprin β, over numerous other metzincins which, if inhibited, would elicit unwanted effects. We recently identified possible molecular starting points for meprin α-specific inhibition through an HTS effort (see part I, preceding paper). In part II we report the optimization of a potent and selective hydroxamic acid meprin α inhibitor probe which may help define the therapeutic potential for small molecule meprin α inhibition and spur further drug discovery efforts in the area of zinc metalloproteinase inhibition.

Synthesis and Structure-Activity Relationships of Pyrazole-based Inhibitors of Meprin α and β

“…This underpins the predicted binding mode of the heteroaromatic inhibitors from previous docking studies, that suggested one phenyl substituent being orientated towards the S1'-subsite. 37 Thus, the lack of interactions of the methyl moiety or a different orientation by the benzyl moiety within the S1'-binding site could lead to a decrease in meprin inhibition. The introduction of a cyclic moiety, directly connected to the pyrazole core is favorable for the inhibition of meprin α and β and might address the S1'-subsite like the phenyl residue found in 7a.…”

“…7a,b & 8a,b), respectively. [36][37][38] The latter monocyclic or fused heteroaromatic derivatives represent the most potent inhibitors of meprins that have been reported to date, even without any functionalization of the actual diaryl-heteroaromatic scaffold.…”