Discovery of Pyridyl Bis(oxy)dibenzimidamide Derivatives
as Selective Matriptase Inhibitors
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Abstract
Matriptase
belongs to trypsin-like serine proteases involved in matrix remodeling/degradation,
growth regulation, survival, motility, and cell morphogenesis. Herein,
we report a structure-based approach, which led to the discovery of
sulfonamide and amide derivatives of pyridyl bis(oxy)benzamidine as
potent and selective matriptase inhibitors. Co-crystal structures
of selected compounds in complex with matriptase supported compound
designing. Additionally, WaterMap analyses indicated the possibility
of occupying a distinct pocket within the catalytic domain, exploration
of which resulted in >100-fold improvement in potency. Co-crystal
structure of <b>10</b> with matriptase revealed critical interactions
leading to potent target inhibition and selectivity against other
serine proteases