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Thrombostatin FM compounds: direct thrombin inhibitors – mechanism of action in vitro and in vivo

Summary.  Background: Novel pentapeptides called Thrombostatin FM compounds consisting mostly of D‐isomers and unusual amino acids were prepared based upon the stable angiotensin converting enzyme breakdown product of bradykinin – RPPGF. Methods and Results: These peptides are direct thrombin inhibitors prolonging the thrombin clotting time, activated partial thromboplastin time, and prothrombin time at ≥0.78, 1.6, and 1.6 μm, respectively. They competitively inhibit α‐thrombin‐induced cleavage of a chromogenic substrate at 4.4–8.2 μm. They do not significantly inhibit plasma kallikrein, factor (F) XIIa, FXIa, FIXa, FVIIa‐TF, FXa, plasmin or cathepsin G. One form, FM19 [rOicPaF(p‐Me)], blocks α‐thrombin‐induced calcium flux in fibroblasts with an IC50 of 6.9 ± 1.2 μm. FM19 achieved 100% inhibition of threshold α‐ or γ‐thrombin‐induced platelet aggregation at 8.4 ± 4.7 μm and 16 ± 4 μm, respectively. The crystal structure of thrombin in complex with FM19 shows that the N‐terminal D‐Arg retrobinds into the S1 pocket, its second residue Oic interacts with His‐57, Tyr‐60a and Trp‐60d, and its C‐terminal p‐methyl Phe engages thrombin’s aryl binding site composed of Ile‐174, Trp‐215, and Leu‐99. When administered intraperitoneal, intraduodenal, or orally to mice, FM19 prolongs thrombin clotting times and delays carotid artery thrombosis. Conclusion: FM19, a low affinity reversible direct thrombin inhibitor, might be useful as an add‐on agent to address an unmet need in platelet inhibition in acute coronary syndromes in diabetics and others who with all current antiplatelet therapy still have reactive platelets.