Thomas Antonsson

The Direct Thrombin Inhibitor Melagatran and Its Oral Prodrug H 376/95: Intestinal Absorption Properties, Biochemical and Pharmacodynamic Effects

UNLABELLED Suboptimal gastrointestinal absorption is a problem for many direct thrombin inhibitors. The studies presented herein describe the new oral direct thrombin inhibitor H 376/95, a prodrug with two protecting residues added to the direct thrombin inhibitor melagatran. Absorption properties in vitro: H 376/95 is uncharged at intestinal pH while melagatran is charged. H 376/95 is 170 times more lipophilic (octanol water partition coefficient) than melagatran. As a result, the permeability coefficient across cultured epithelial Caco-2 cells is 80 times higher for H 376/95 than for melagtran. Pharmacokinetic studies in healthy volunteers: H 376/95 is converted to melagatran in man. Oral bioavailability, measured as melagatran in plasma, is about 20% after oral administration of H 376/95, which is 2.7-5.5 times higher than after oral administration of melagatran. The variability in the area under the drug plasma concentration vs. time curve (AUC) is much smaller with oral H 376/95 (coefficient of variation 20%) than with oral melagatran (coefficient of variation 38%). Pharmacodynamic properties: H 376/95 is inactive towards human alpha-thrombin compared with melagatran [inhibition constant (K(i)) ratio, 185 times], a potential advantage for patients with silent gastrointestinal bleeding. In an experimental thrombosis model in the rat, oral H 376/95 was more effective than the subcutaneous low molecular weight heparin dalteparin in preventing thrombosis. CONCLUSION By the use of the prodrug principle, H 376/95 endows the direct thrombin inhibitor melagatran with pharmacokinetic properties required for oral administration without compromising the promising pharmacodynamic properties of melagatran.

A new oral anticoagulant: the 50-year challenge

It is rare for any drug introduced more than 50 years ago to remain unsurpassed today; yet the oral prevention and treatment of thrombosis are still achieved by the use of the vitamin K antagonists (coumarins), such as warfarin, which were introduced in the 1940s and 1950s. For these anticoagulants, careful monitoring of the effect is needed to avoid bleeding or loss of efficacy. On the basis of the need for improved oral anticoagulants, a goal was set in 1985 to develop a new oral anticoagulant that could replace the vitamin K antagonists. After providing some medical and historical context, this article discusses the challenges facing the multidisciplinary team of scientists who were involved in the project leading to the discovery of the anticoagulant ximelagatran (Exanta; AstraZeneca), the first oral direct thrombin inhibitor.

Lead Optimization of Ethyl 6-Aminonicotinate Acyl Sulfonamides as Antagonists of the P2Y12 Receptor. Separation of the Antithrombotic Effect and Bleeding for Candidate Drug AZD1283

Synthesis and structure-activity relationships of ethyl 6-aminonicotinate acyl sulfonamides, which are potent antagonists of the P2Y12 receptor, are presented. Shifting from 5-chlorothienyl to benzyl sulfonamides significantly increased the potency in the residual platelet count assay. Evaluation of PK parameters in vivo in dog for six compounds showed a 10-fold higher clearance for the azetidines than for the matched-pair piperidines. In a modified Folts model in dog, both piperidine 3 and azetidine 13 dose-dependently induced increases in blood flow and inhibition of ADP-induced platelet aggregation with antithrombotic ED50 values of 3.0 and 10 μg/kg/min, respectively. The doses that induced a larger than 3-fold increase in bleeding time were 33 and 100 μg/kg/min for 3 and 13, respectively. Thus, the therapeutic index (TI) was ≥ 10 for both compounds. On the basis of these data, compound 3 was progressed into human clinical trials as candidate drug AZD1283.

Optimization of ketone-based P2Y12 receptor antagonists as antithrombotic agents: Pharmacodynamics and receptor kinetics considerations

Modification of a series of P2Y12 receptor antagonists by replacement of the ester functionality was aimed at minimizing the risk of in vivo metabolic instability and pharmacokinetic variability. The resulting ketones were then optimized for their P2Y12 antagonistic and anticoagulation effects in combination with their physicochemical and absorption profiles. The most promising compound showed very potent antiplatelet action in vivo. However, pharmacodynamic-pharmacokinetic analysis did not reveal a significant separation between its anti-platelet and bleeding effects. The relevance of receptor binding kinetics to the in vivo profile is described.

A SPECIFIC ANTIDOTE FOR TICAGRELOR

A Fab, MEDI2452, is being developed as an antidote for ticagrelor patients requiring urgent surgery or experiencing major or life-threatening bleeding where ticagrelor reversal may be desirable. MEDI2452 was isolated and optimized by human antibody phage display. The affinity was measured by KinExA