Pharmacokinetics of an emerging new class of anticoagulant/antithrombotic drugs

Abstract

Small-molecule direct thrombin inhibitors represent a new class of anticoagulants and are emerging as antithrombotic drugs with a range of indications. The tripeptide type or peptidomimetic compounds, including argatroban, efegatran, inogatran and napsagatran, hitherto clinically studied represent a first generation of thrombin inhibitors that are pharmacokinetically characterised by relatively rapid hepato-biliary clearance and short half-lives necessitating their administration as intravenous infusion. They are not orally bioavailable because of poor enteral absorption and presystemic hepatic extraction. Melagatran can be administered subcutaneously, and a prodrug form of melagatran, ximelagatran, is at present the only oral thrombin inhibitor available. Direct thrombin inhibitors produce predictable, stable and rapidly reversible anticoagulation measurable by common coagulation assays. Significant pharmacokinetic drug-drug interactions have not been reported. Possible pharmacodynamic interactions, in terms of prolongation of plasma clotting times, with other anticoagulant drugs must be taken into account when monitoring direct thrombin inhibitors using coagulation assays.

Principles of Enzyme‐Inhibitor Design

“…Until more results of early-phase clinical trials are published, it will not be clear whether the problem is that thrombin is a difficult drug target, e.g., because of bleeding risks, or whether the inhibitors proposed as clinical candidates simply do not have sufficiently drug-like properties. The suspicion is that tripeptide analogues with a strongly basic group have intrinsically poor pharmacokinetic and pharmacodynamic properties [8]. If this is true, new and different inhibitors are needed, and here a good understanding of the interactions between the inhibitor and the enzyme active site can contribute significantly to the identification of inhibitor molecules suitable for development as drugs.…”

“…Here we will concentrate only on the molecular recognition aspects. Comprehensive surveys of the thrombin inhibitor patent literature have been made by Wiley and Fisher (pre-1997) [1] and Coburn (1997Coburn ( -2000 [2], and the clinical use of direct thrombin inhibitors has been extensively reviewed [3][4][5][6][7][8][9][10][11]. Thrombin residue numbering follows throughout the chymotrypsinogen convention.…”

Preparation of Methyl Ester Precursors of Biologically Active Agents

“…Ester formation can also be applied to pharmaceutical agents to modify their pharmacokinetics or ease of administration as another application of this "pro-drug" strategy. It has been applied to many known drugs (14) such as ramipril/ramiprilat (5,6) and melagatran/ximelagatran (7,8), and to the compounds studied here, aspirin and indomethacin (913). …”

Bioanalytical method development and validation for simultaneous estimation of (R)- and (S)-isomers of S002-333: a potent novel anti-thrombotic agent using LC–MS/MS

“…In the United States, mortality related to cardiovascular diseases approaches one million people per year, with a high proportion resulting as a consequence of thrombotic processes. Current available treatment for venous thrombosis and embolic disease include anticoagulants (warfarin and other coumarin derivatives, heparin and low molecular mass heparin) which although effective, have either a narrow therapeutic index (i.e., warfarin) or require administration by injection (i.e., heparin, low molecular mass heparin) (Betz, 2001;Hauptmann, 2002;Pinto et al, 2001). In quest for safe and effective anti-thrombotic agent, S002-333 [2-(4-methoxybenzenesulfonyl)-2,3,4,9-tetrahydro-1H-b-carboxylic acid amide] (Fig.…”