title: Design, synthesis, and SAR of a series of activated protein C (APC) inhibitors with selectivity against thrombin for the treatment of haemophilia.
abstract: A design strategy was used to identify inhibitors of activated protein C with selectivity over thrombin featured by a basic and/or aromatic functionality for binding to the S2 pocket. Our strongest inhibitor showed an IC50-material value and selectivity for APC vs thrombin similar to a compound previously reported in the literature. However, in contrast to the reference compound, our compound showed a retained coagulant effect of thrombin with increasing substrate concentration in a modified Calibrated Automated Thrombogram (CAT) method. This was likely related to our compound being inactive against FVIIa, while the reference compound showed an IC50 of 8.9 μM. Thus, the higher selectivity of our compound against all relevant coagulation factors likely explained its higher therapeutic potential in comparison to the reference compound. The data indicate that at least a 100-fold selectivity over other serine proteases in the coagulation cascade will be required for an effective APC inhibitor.
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca R&D, CVMD iMed, Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden. Electronic address: bach@chalmers.se.
authors.forename: Peter
authors.initials: P
authors.lastname: Bach
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca R&D, CVMD iMed, Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden. Electronic address: laurent.knerr@astrazeneca.com.
authors.forename: Laurent
authors.initials: L
authors.lastname: Knerr
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca R&D, CVMD iMed, Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Fjellström
authors.affiliation: Department of Bioscience, AstraZeneca R&D, CVMD iMed, Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Kenny
authors.initials: K
authors.lastname: Hansson
authors.affiliation: Department of Bioscience, AstraZeneca R&D, CVMD iMed, Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Mattsson
authors.affiliation: Department of Bioscience, AstraZeneca R&D, CVMD iMed, Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Gustafsson
mesh_terms: D001665:Binding Sites; D003029:Coagulants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006467:Hemophilia A / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D011485:Protein Binding / Q000187:drug effects; D018046:Protein C Inhibitor / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013917:Thrombin / Q000037:antagonists & inhibitors*
chemical_list: D003029:Coagulants; D018046:Protein C Inhibitor; D013917:Thrombin
keywords: Activated Protein C (APC); Haemophilia; Inhibitor; S2 pocket; Solid-phase synthesis; Thrombin