PubMed · 11877821
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J Kivisaari. 1999. [Fast speed?].. https://pubmed.ncbi.nlm.nih.gov/11877821/
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A solution-phase synthesis of an alpha-ketothiazole library of the general form D-Phe-L-AA-L-Arg-alpha-ketothiazole is described. The five-step synthesis is accomplished using a combination of polymeric reagents and polymer-assisted solution-phase purification protocols, including reactant-sequestering resins, reagent-sequestering resins, and tagged reagents. The multi-step synthesis affords the desired alpha-ketothiazole products in excellent purities and yields. A variety of L-amino acid inputs were used to probe the S2 pocket of the tissue factor (TF) VIIa enzyme to influence both potency and selectivity. An X-ray crystal structure of compound 10e bound to the TF/VIIa complex was obtained that explains the observed selectivity. The alpha-ketothiazoles were found to be potent, reversible-covalent inhibitors of tissue factor VIIa, with some analogues demonstrating selectivity versus thrombin.
Heparin and the vitamin K antagonist warfarin have been in clinical use for more than 50 years. However, both are associated with several well-documented drawbacks that limit their use. Warfarin can be administered orally, making it the agent of choice for long-term management of thromboembolic conditions, but frequent coagulation monitoring is necessary because of its unpredictable anticoagulant effect--the result, in part, of food and drug interactions-and its narrow therapeutic window. Heparin and low-molecular-weight heparin (LMWH) can be administered parenterally only. Coagulation monitoring is also required with heparin although not with LMWH, due to reduced levels of plasma protein binding. In the last 10 years, in the quest to develop new agents that are at least as effective as those currently available, with improved safety and greater ease of use, anticoagulants that target almost every step in the coagulation pathway have been developed. These include inhibitors of the factor VIIa (FVIIa)/tissue factor complex, FIXa inhibitors, direct and antithrombin-dependent FXa inhibitors, agents that enhance the protein C anticoagulant pathway, and direct thrombin inhibitors (DTIs) that inhibit the activity of thrombin. Of the new agents, three DTIs-hirudin, bivalirudin, and argatroban-and the synthetic pentasaccharide (Arixtra) are approved for clinical use. Three other new agents-activated protein C (APC), tissue factor pathway inhibitor (TFPI), and the oral DTI ximelagatran (Exanta, AstraZeneca)-have been evaluated in Phase III studies. The mechanism of action and properties of these new anticoagulants and their potential to replace those in current use will be reviewed here.
CONTEXT: The expression and release of tissue factor is a major trigger for the activation of coagulation in patients with sepsis. Tissue factor pathway inhibitor (TFPI) forms a complex with tissue factor and blood protease factors leading to inhibition of thrombin generation and fibrin formation. OBJECTIVES: To determine if administration of tifacogin (recombinant TFPI) provides mortality benefit in patients with severe sepsis and elevated international normalized ratio (INR) and to assess tifacogin safety in severe sepsis, including patients with low INR. DESIGN AND SETTING: A randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trial conducted from March 21, 2000, through September 27, 2001, in 245 hospitals in 17 countries in North America, Europe, and Israel. PATIENTS: The primary efficacy population consisted of 1754 patients (> or =18 years) with severe sepsis and a high INR (> or =1.2) randomly assigned to intravenous infusion of either tifacogin (0.025 mg/kg per hour for 96 hours, n = 880) or placebo (arginine citrate buffer, n = 874), and 201 patients with a low INR (<1.2) randomly assigned to receive the same dose of either tifacogin or placebo. MAIN OUTCOME MEASURE: All-cause 28-day mortality. RESULTS: Overall mortality at 28 days in the tifacogin-treated group (n = 880) vs the placebo group (n = 874) for high INR was 34.2% vs 33.9%, respectively (P =.88, Pearson chi2 test; P =.75, logistic regression model). None of the protocol-specified secondary end points differed between the tifacogin vs placebo groups. An analysis on the first 722 patients demonstrated a mortality rate of 38.9% for placebo vs 29.1% for tifacogin (P =.006, Pearson chi2 test). Tifacogin significantly attenuated prothrombin fragment 1.2 and thrombin:antithrombin complex levels (P<.001, 2-sample t test) in patients with high and low INR. Overall mortality was lower in the tifacogin response in patients with low INR (12%; n = 83) vs placebo (22.9%; n = 118) (P =.051, Pearson chi2 test; P =.03, logistic regression model). There was an increase in serious adverse events with bleeding in the tifacogin group in both cohorts (6.5% tifacogin and 4.8% placebo for high INR; 6.0% tifacogin and 3.3% placebo for low INR). CONCLUSIONS: Treatment with tifacogin had no effect on all-cause mortality in patients with severe sepsis and high INR. Tifacogin administration was associated with an increase in risk of bleeding, irrespective of baseline INR.