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

Rajeev Goswami; Subhendu Mukherjee; Gerd Wohlfahrt; Chakshusmathi Ghadiyaram; Jwala Nagaraj; Beeram Ravi Chandra; Ramesh K Sistla; Leena K Satyam; Dodheri S Samiulla; Anu Moilanen; Hosahalli S Subramanya; Murali Ramachandra

doi:10.1021/ml400213v

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

ACS Med Chem Lett. 2013 Oct 7;4(12):1152-7. doi: 10.1021/ml400213v. eCollection 2013 Dec 12.

Affiliations

¹ Aurigene Discovery Technologies Limited , 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
² Orion Corporation , Orionintie 1, FIN-02101 Espoo, Finland.
³ Orion Corporation , Tengströminkatu 8, FIN-20101 Turku, Finland.

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.

Keywords: Matriptase; SAR; cancer; crystal structure; pyridyl dibenzimidamide.