Thrombin bifunctional

Because of their high selectivity against other serine proteases, for example thrombin, trypsin, or factor Xa, the development of bifunctional tryptase inhibitors has attracted much attention during recent years. Several classes of effective dibasic tryptase inhibitor have been reported, recently [13,14, 23], Herein, we describe syn-... 

We have created efficient syntheses of remarkably potent and selective bifunctional tryptase inhibitors, which are also competitive and reversible, containing pyran moieties and hetero and non-hetero aryl diynes as scaffolds. Several modifications at the core templates and the linker moieties are well tolerated without significant loss of inhibition activity. In contrast with previous results published recently [32], it was also apparent from the aryl diyne inhibitors that the distance between the two terminal amino groups can be considerably less than 30 bonds in highly potent target compounds (e.g. 9 and 29 with 26 bonds each). The in-vitro potencies of the compounds were between 1 im for 26 and 1.3 nM for 15 with high selectivity against other serine proteases (trypsin, thrombin, and factor Xa, respectively) in... 

The in vivo efficacy of the bifunctional thrombin inhibitors 4 and 7 was also assessed in a chemically-induced thrombosis model where deep arterial injury to the rat carotid artery is mediated by FeCb [79]. Stenosis of the blood vessel resulting from FeCb-mediated injury results in decreased blood flow and an abrupt temperature drop across the stenosed area due to arterial occlusion. Both bifunctional thrombin inhibitors 4 and 7 doubled the mean occlusion time (MOT) at an i.v. bolus dose of 1 mg/kg. At a dose of 2 mg/kg i.v. of compound 7, the vessel remained patent for over 60 minutes compared to saline treated control rats (MOT = 19 1 minute), r-hirudin was slightly more potent, doubling the mean occlusion time at an i.v. dose of 0.5 mg/kg. 

Aptamer recognition has been described for the development of biosensors and applied to biomedical and environmental studies [46]. As illustrated in Fig. 5.7, an electrochemical aptamer-based sensor (E-AB) for specific recognition of thrombin was constructed. Zhang and co-workers [46] used immobilization of a Fe304-nanoparticles/tagged aptamer via a self-assembly method. In this case, bifunctional aptamer was covalently linked to both Fe304-NPs and gold electrode. Certainly... 

---