title: Antiplatelet and antithrombotic effect of F 16618, a new thrombin proteinase-activated receptor-1 (PAR1) antagonist.
abstract: OBJECTIVE
  New antithrombotic agents with the potential to prevent atherothrombotic complications are being developed to target receptors on platelets and other cells involved in plaque growth. The aim of this study was to investigate the antiplatelet effects of F 16618, a new non-peptidic PAR1 (thrombin receptor) antagonist.
  
  
  METHODS
  We investigated the inhibitory effect of F 16618 on human platelet aggregation ex vivo, in whole blood and washed platelets, by using a multiple-electrode platelet aggregometer based on impedance and an optical aggregometer, respectively. Its effects on whole-blood haemostasis (clot parameters) were analysed with the ROTEM thromboelastometry device and the platelet function analyser PFA-100. A guinea-pig model of arterial thrombosis was used to investigate its effects on thrombus formation in vivo.
  
  
  RESULTS
  F 16618 inhibited PAR1 agonist peptide (SFLLR-peptide)-induced washed platelet aggregation ex vivo. This effect was concentration-dependent and exhibited a competitive inhibition profile. Washed platelet aggregation, as well as P-selectin expression induced by thrombin, were significantly inhibited by 10 µM F 16618. In whole-blood experiments, 20 µM F 16618 inhibited SFLLR-induced platelet aggregation by 49%. In contrast, it had no effect on whole-blood haemostasis. In the guinea-pig model of carotid thrombosis, 0.32 mg·kg(-1) F 16618 doubled the occlusion time.
  
  
  CONCLUSIONS
  F 16618 was shown to have strong antithrombotic activity in vivo and moderate antiplatelet effects ex vivo. As these effects were not associated with major effects on physiological haemostasis, this molecule is a good antiplatelet drug candidate for use either alone or in combination with current treatments.
authors.affiliation: Inserm UMR S 765, Faculté de Pharmacie, Paris, FranceUniversité Paris Descartes, Sorbonne Paris Cité, Paris, FranceCentre de Recherche Pierre Fabre, 17, Avenue Jean Moulin, Castres cedex, FranceAP-HP, Hôpital Européen Georges Pompidou, Service d'Hématologie Biologique, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Dumas
authors.affiliation: Inserm UMR S 765, Faculté de Pharmacie, Paris, FranceUniversité Paris Descartes, Sorbonne Paris Cité, Paris, FranceCentre de Recherche Pierre Fabre, 17, Avenue Jean Moulin, Castres cedex, FranceAP-HP, Hôpital Européen Georges Pompidou, Service d'Hématologie Biologique, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Nadal-Wollbold
authors.affiliation: Inserm UMR S 765, Faculté de Pharmacie, Paris, FranceUniversité Paris Descartes, Sorbonne Paris Cité, Paris, FranceCentre de Recherche Pierre Fabre, 17, Avenue Jean Moulin, Castres cedex, FranceAP-HP, Hôpital Européen Georges Pompidou, Service d'Hématologie Biologique, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Gaussem
authors.affiliation: Inserm UMR S 765, Faculté de Pharmacie, Paris, FranceUniversité Paris Descartes, Sorbonne Paris Cité, Paris, FranceCentre de Recherche Pierre Fabre, 17, Avenue Jean Moulin, Castres cedex, FranceAP-HP, Hôpital Européen Georges Pompidou, Service d'Hématologie Biologique, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Perez
authors.affiliation: Inserm UMR S 765, Faculté de Pharmacie, Paris, FranceUniversité Paris Descartes, Sorbonne Paris Cité, Paris, FranceCentre de Recherche Pierre Fabre, 17, Avenue Jean Moulin, Castres cedex, FranceAP-HP, Hôpital Européen Georges Pompidou, Service d'Hématologie Biologique, Paris, France.
authors.forename: T
authors.initials: T
authors.lastname: Mirault
authors.affiliation: Inserm UMR S 765, Faculté de Pharmacie, Paris, FranceUniversité Paris Descartes, Sorbonne Paris Cité, Paris, FranceCentre de Recherche Pierre Fabre, 17, Avenue Jean Moulin, Castres cedex, FranceAP-HP, Hôpital Européen Georges Pompidou, Service d'Hématologie Biologique, Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Létienne
authors.affiliation: Inserm UMR S 765, Faculté de Pharmacie, Paris, FranceUniversité Paris Descartes, Sorbonne Paris Cité, Paris, FranceCentre de Recherche Pierre Fabre, 17, Avenue Jean Moulin, Castres cedex, FranceAP-HP, Hôpital Européen Georges Pompidou, Service d'Hématologie Biologique, Paris, France.
authors.forename: T
authors.initials: T
authors.lastname: Bourbon
authors.affiliation: Inserm UMR S 765, Faculté de Pharmacie, Paris, FranceUniversité Paris Descartes, Sorbonne Paris Cité, Paris, FranceCentre de Recherche Pierre Fabre, 17, Avenue Jean Moulin, Castres cedex, FranceAP-HP, Hôpital Européen Georges Pompidou, Service d'Hématologie Biologique, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Grelac
authors.affiliation: Inserm UMR S 765, Faculté de Pharmacie, Paris, FranceUniversité Paris Descartes, Sorbonne Paris Cité, Paris, FranceCentre de Recherche Pierre Fabre, 17, Avenue Jean Moulin, Castres cedex, FranceAP-HP, Hôpital Européen Georges Pompidou, Service d'Hématologie Biologique, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Le Grand
authors.affiliation: Inserm UMR S 765, Faculté de Pharmacie, Paris, FranceUniversité Paris Descartes, Sorbonne Paris Cité, Paris, FranceCentre de Recherche Pierre Fabre, 17, Avenue Jean Moulin, Castres cedex, FranceAP-HP, Hôpital Européen Georges Pompidou, Service d'Hématologie Biologique, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Bachelot-Loza
mesh_terms: D000818:Animals; D002341:Carotid Artery Thrombosis / Q000188:drug therapy; D003094:Collagen / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006168:Guinea Pigs; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D044463:Receptor, PAR-1 / Q000819:agonists; D013917:Thrombin / Q000494:pharmacology
chemical_list: C542252:2-(5-oxo-5-(4-pyridin-2-ylpiperazin-1-yl)penta-1,3-dienyl)benzonitrile; C090291:C186 65; D005343:Fibrinolytic Agents; D009842:Oligopeptides; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D044463:Receptor, PAR-1; D003094:Collagen; D013917:Thrombin