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Discovery of Pyridyl Bis(oxy)dibenzimidamide Derivatives as Selective Matriptase Inhibitors.

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 10 with matriptase revealed critical interactions leading to potent target inhibition and selectivity against other serine proteases.

SUBMITTER: Goswami R

PROVIDER: S-EPMC4027570 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Discovery of Pyridyl Bis(oxy)dibenzimidamide Derivatives as Selective Matriptase Inhibitors.

Goswami Rajeev R Mukherjee Subhendu S Wohlfahrt Gerd G Ghadiyaram Chakshusmathi C Nagaraj Jwala J Chandra Beeram Ravi BR Sistla Ramesh K RK Satyam Leena K LK Samiulla Dodheri S DS Moilanen Anu A Subramanya Hosahalli S HS Ramachandra Murali M

ACS medicinal chemistry letters 20131007 12

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 possibi ...[more]

PMID: 24900621

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