title: Discovery of highly potent small molecule kallikrein inhibitors.
abstract: Uncontrolled kallikrein activation is involved in diseases such as hereditary angioedema, bacterial septic shock and procedures such as cardiopulmonary bypass. Here we report a series of small molecule compounds that potently inhibit kallikrein activity in vitro. Kinetic studies indicate that some of these compounds are slow binding inhibitors of kallikrein with Ki final less than a nanomolar. The ability of these compounds to inhibit the activity of kallikrein was further confirmed in a plasma model by quantitating the release of bradykinin, an endogenous cleavage product of plasma kallikrein. To understand the inhibitory mechanism of the selected compounds toward kallikrein, the interactions between the selected compounds and kallikrein was explored using molecular modeling based on the information of crystal structures of TF/FVIIa and kallikrein. The information presented in the current study provides an initial approach to develop more selective and therapeutically useful small molecule inhibitors.
authors.affiliation: Biology Department, BioCryst Pharmaceuticals, Inc. 2190 Parkway Lake Drive, Birmingham, Alabama 35244, USA. jzhang@biocryst.com
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: R
authors.initials: R
authors.lastname: Krishnan
authors.forename: C S
authors.initials: CS
authors.lastname: Arnold
authors.forename: E
authors.initials: E
authors.lastname: Mattsson
authors.forename: J M
authors.initials: JM
authors.lastname: Kilpatrick
authors.forename: S
authors.initials: S
authors.lastname: Bantia
authors.forename: A
authors.initials: A
authors.lastname: Dehghani
authors.forename: B
authors.initials: B
authors.lastname: Boudreaux
authors.forename: S N
authors.initials: SN
authors.lastname: Gupta
authors.forename: P L
authors.initials: PL
authors.lastname: Kotian
authors.forename: P
authors.initials: P
authors.lastname: Chand
authors.forename: Y S
authors.initials: YS
authors.lastname: Babu
mesh_terms: D001920:Bradykinin / Q000032:analysis; D020134:Catalytic Domain; D015942:Factor VIIa; D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007700:Kinetics; D008958:Models, Molecular; D010949:Plasma / Q000378:metabolism; D011485:Protein Binding; D013925:Thromboplastin
chemical_list: D013925:Thromboplastin; D007610:Kallikreins; D015942:Factor VIIa; D001920:Bradykinin