title: 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.
authors.affiliation: Aurigene Discovery Technologies Limited , 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Goswami
authors.affiliation: Aurigene Discovery Technologies Limited , 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
authors.forename: Subhendu
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Orion Corporation , Orionintie 1, FIN-02101 Espoo, Finland.
authors.forename: Gerd
authors.initials: G
authors.lastname: Wohlfahrt
authors.affiliation: Aurigene Discovery Technologies Limited , 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
authors.forename: Chakshusmathi
authors.initials: C
authors.lastname: Ghadiyaram
authors.affiliation: Aurigene Discovery Technologies Limited , 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
authors.forename: Jwala
authors.initials: J
authors.lastname: Nagaraj
authors.affiliation: Aurigene Discovery Technologies Limited , 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
authors.forename: Beeram Ravi
authors.initials: BR
authors.lastname: Chandra
authors.affiliation: Aurigene Discovery Technologies Limited , 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Sistla
authors.affiliation: Aurigene Discovery Technologies Limited , 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
authors.forename: Leena K
authors.initials: LK
authors.lastname: Satyam
authors.affiliation: Aurigene Discovery Technologies Limited , 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
authors.forename: Dodheri S
authors.initials: DS
authors.lastname: Samiulla
authors.affiliation: Orion Corporation , Tengströminkatu 8, FIN-20101 Turku, Finland.
authors.forename: Anu
authors.initials: A
authors.lastname: Moilanen
authors.affiliation: Aurigene Discovery Technologies Limited , 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
authors.forename: Hosahalli S
authors.initials: HS
authors.lastname: Subramanya
authors.affiliation: Aurigene Discovery Technologies Limited , 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
authors.forename: Murali
authors.initials: M
authors.lastname: Ramachandra
keywords: Matriptase; SAR; cancer; crystal structure; pyridyl dibenzimidamide