Factor VIIa inhibitors: Chemical optimization, preclinical pharmacokinetics, pharmacodynamics, and efficacy in an arterial baboon thrombosis model

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 7, 2006, Pages 2037-2041

  Young, Wendy B ^a   Mordenti, Joyce ^a   Torkelson, Steven ^a   Shrader, William D ^a   Kolesnikov, Aleksandr ^a   Rai, Roopa ^a   Liu, Liang ^a   Hu, Huiyong ^a   Leahy, Ellen M ^a   Green, Michael J ^a   Sprengeler, Paul A ^a   Katz, Bradley A ^a   Yu, Christine ^a   Janc, James W ^a   Elrod, Kyle C ^a   Marzec, Ulla M ^b,c   Hanson, Stephen R ^b,c  

^a CELERA   (United States)

^b EMORY UNIVERSITY   (United States)

^c OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

Author keywords

Antithrombotic; Baboon thrombosis model; Coagulation; Factor VIIa; Factor Xa; fVIIa; Pharmacodynamics; Pharmacokinetics; Serine protease; TF; Thrombin; Tissue factor

Indexed keywords

BLOOD CLOTTING FACTOR 7A INHIBITOR; ENOXAPARIN; HEPARIN;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTERY THROMBOSIS; ARTICLE; BABOON; CONTROLLED STUDY; DOSE RESPONSE; DRUG EFFICACY; DRUG POTENCY; DRUG SELECTIVITY; EXPERIMENTAL MODEL; FIBRIN DEPOSITION; NONHUMAN; PHARMACODYNAMICS; SPECIES; STRUCTURE ACTIVITY RELATION; THROMBOCYTE; THROMBOCYTE AGGREGATION INHIBITION;

ANIMALS; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; CRYSTALLOGRAPHY, X-RAY; FACTOR VIIA; MODELS, ANIMAL; MODELS, MOLECULAR; PAPIO; SERINE PROTEINASE INHIBITORS; THROMBOSIS;

ANIMALIA; PAPIO HAMADRYAS;

EID: 33144456767     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.12.059     Document Type: Article

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19. 2. Coagulation experiments were carried out in human plasma using a Beckman Coulter ACL100 in accordance with the manufacturer's instructions
20. Analog 9 was evaluated in the HitProfilingScreen™ at MDS Pharma Services, Bothell, WA 98021.
21. Analog 9 was evaluated in the Ames Salmonella Mutagenicity Test with two mutant strains of Salmonella typhimurium LT2 (i.e., TA98 and TA100) with and without S9 activation at MDS Pharma Services, Taipei, Taiwan.
22. The PDB access code for the X-ray coordinates is 2B7D.
23. Plasma concentrations of 9 were assayed by LC/MS/MS. Pharmacokinetic data were analyzed by WinNonlin-Pro (Pharsight Corp.), using a two-compartment model.
24. b, where Y is the pharmacokinetic parameter of interest, W is the body weight, a is the y-intercept, and b is the slope obtained from the plot of log Y versus log W (as illustrated in Fig. 2 for clearance parameter). See J. Mordenti J. Pharm. Sci. 75 1986 1028 for details
25. The animal experiments were approved by the Institutional Animal Care and Use Committee of Emory University in accordance with the United States federal guidelines. Thrombosis was initiated at a predetermined time after drug administration by interposing a thrombogenic device into a chronic femoral arterio-venous (A-V) shunt in conscious non-anticoagulated baboons. For analog 9 and heparin, thrombosis was initiated 5 min after IV bolus dosing (in the heparin group, an infusion continued throughout the experiment); whereas for enoxaparin, thrombosis was initiated 90 min after SC dosing. The thrombogenic device consisted of a 2 cm segment of porous expanded (poly)tetrafluoroethylene vascular graft (ePTFE, 4 mm id) filled with relipidated tissue factor. Blood flow was maintained at 100 mL/min, generating a wall shear rate of 265/s. Thrombus was monitored dynamically for 60 min by gamma camera imaging of autologous 111-indium (111-In)-labeled platelets. Images were acquired at 5 min intervals. Total platelet deposition was calculated at each time point by dividing the thrombus radioactivity (cpm) by the blood specific activity (cpm/mL) and multiplying by the blood platelet count (platelets/mL). Fibrin deposition was monitored by injecting a trace amount of 125-iodine (125-I)-labeled autologous fibrinogen 10 min before the start of the study, then saving the thrombus that formed in the graft for 30 days to permit decay of 111-In activity. The 125-I activity was measured in a gamma well counter. 125-I activity was converted to total deposited fibrin (mg) using values for the specific activity of plasma-clottable fibrinogen and the plasma fibrinogen concentration that were obtained at the time of the study. Template bleeding times (BT) were measured on a shaved forearm prior to dosing and at 30 min after initiation of thrombosis. The PT and aPTT were monitored throughout the study.
26. 50 = plasma concentration of 9 required to produce 50% of the maximum effect, and γ = sigmoidicity or shape parameter. When dose (D) is evaluated, C is replaced by D (mg/kg) in the equation.