title: The antithrombotic and anti-inflammatory effects of BCX-3607, a small molecule tissue factor/factor VIIa inhibitor.
abstract: Tissue factor (TF) is a transmembrane glycoprotein that binds its zymogen cofactor, Factor VIIa (FVIIa) on the cell surface. Together (TF/FVIIa) they activate Factor X (FX) and Factor IX (FIX) and start the extrinsic pathway of blood coagulation. As such, the TF/FVIIa complex plays an important role in normal physiology as well as in thrombotic diseases such as unstable angina (UA), disseminated intravascular coagulation (DIC), and deep vein thrombosis (DVT). In addition to its function as an initiator of coagulation, TF/FVIIa plays an important role in inflammation. Expression of TF on the cell surface and its appearance as a soluble molecule are characteristic features of acute and chronic inflammation in conditions such as sepsis and atherosclerosis. Here we demonstrate that BCX-3607, a small molecule potent inhibitor of TF/FVIIa, reduces thrombus weight in an animal model of DVT. BCX-3607 also decreases the level of interleukin-6 (IL-6) in a LPS-stimulated mouse model of endotoxemia. Additionally, in vitro studies indicate that BCX-3607 blocks the generation of TF/FVIIa-induced IL-8 mRNA in human keratinocytes and reduces the TF/FVIIa-mediated generation of IL-6 and IL-8 in human umbilical vein endothelial cells (HUVEC). Therefore, BCX-3607 might block the TF/FVIIa-mediated coagulation and inflammation associated with pathological conditions.
authors.affiliation: BioCryst Pharmaceuticals, Inc., 2190 Parkway Lake Drive, Birmingham, AL 35244, USA. sarnold@biocryst.com
authors.forename: C Shane
authors.initials: CS
authors.lastname: Arnold
authors.forename: Cynthia
authors.initials: C
authors.lastname: Parker
authors.forename: Ramanda
authors.initials: R
authors.lastname: Upshaw
authors.forename: Hans
authors.initials: H
authors.lastname: Prydz
authors.forename: Pooran
authors.initials: P
authors.lastname: Chand
authors.forename: Pravin
authors.initials: P
authors.lastname: Kotian
authors.forename: Shanta
authors.initials: S
authors.lastname: Bantia
authors.forename: Y Sudhakar
authors.initials: YS
authors.lastname: Babu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D050197:Atherosclerosis / Q000188:drug therapy; D015152:Blotting, Northern; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism; D019446:Endotoxemia / Q000473:pathology; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D051379:Mice; D008954:Models, Biological; D008956:Models, Chemical; D011517:Prothrombin Time; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis; D013925:Thromboplastin / Q000037:antagonists & inhibitors*; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; C510686:BCX-3607; D005343:Fibrinolytic Agents; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D011725:Pyridines; D012333:RNA, Messenger; D013925:Thromboplastin; D015942:Factor VIIa