By Elisabeth Perzborn (formerly Pharma R&D Discovery Research Bayer AG, Germany)
Heparins and VKA have been the mainstay of anticoagulant therapy for more than 60 years. These traditional anticoagulant agents, affecting multiple coagulation factors, are associated with several limitations. These shortcomings have spurred the search for oral small-molecule inhibitors that specifically target directly a single coagulation factor, such as factor Xa (FXa) or thrombin resulting in a dramatic change of the landscape of anticoagulation by NOAKs (non-vitamin K-antagonistic oral anticoagulants). The direct thrombin inhibitor dabigatran (Pradaxa®) and the direct Factor Xa (FXa) inhibitors, rivaroxaban (Xarelto®), apixaban (Eliquis®) and edoxaban (Lixiana®, Savaysa®) are the first alternative to VKA for oral anticoagulation. Rivaroxaban was the first oral FXa inhibitor licensed for VTE prevention and treatment.
This overview summarizes the history of rivaroxaban, focusing on the rationale of the preclinical FXa program, compound finding and chemical optimization program, shows how we succeeded in the synthesis of rivaroxaban, and gives a brief overview of the pharmacological profile of rivaroxaban.
The serine protease FXa was selected as target as it is known to be the primary site of amplification in the coagulation process (i.e. one molecule of FXa produced about 1000 molecules of thrombin). When we initiated the FXa program in 1998, no orally active FXa inhibitors with sufficient antithrombotic activity were known. All known potent inhibitors contained highly basic, positively charged residues, such as amidines, which act as mimics for an arginine present in prothrombin, the natural substrate of FXa. However, strongly basic residues contribute to poor oral absorption.
High-throughput screening of approximately 200,000 compounds revealed several hits that selectively inhibited the cleavage of a chromogenic substrate by human FXa.1
The chemical optimization started with the most potent hit. However, we could not achieve the target pharmacokinetic profile, as compounds with high potency showed generally low bioavailability. But we learned that the non-basic chlorothiophene moiety was essential for potent FXa inhibition. When re-evaluating the HTS hits by similarity considerations, we identified oxazolidinone derivatives containing a thiophene moiety as weak FXa inhibitors with good oral bioavailability. Applying our experience we introduced the chlorothiophene moiety resulting in a lead compound with more than 200-fold improved potency and high oral bioavailability and which did not comprise a basic group. This significant breakthrough led to the synthesis of rivaroxaban in 2000.
The mode of action of rivaroxaban is the direct, selective and competitive inhibition of human FXa.2 In various well-established preclinical animal models of venous and arterial thrombosis, rivaroxaban showed dose dependent antithrombotic activity. Rivaroxaban has shown predictable pharmacokinetics and pharmacodynamics across a wide range of doses in healthy individuals.3
The encouraging findings from preclinical and early clinic studies led to the investigation of rivaroxaban in late clinical studies for the prevention and treatment of thromboembolic diseases. 275,000 patients were included in the study program. Across all indications rivaroxaban is approved in more than 130 countries.
REFERENCES
- Roehrig S, Straub A, Pohlmann J, Lampe T, Pernerstorfer J, Schlemmer KH, Reinemer P, Perzborn E. Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5- yl}methyl)thiophene- 2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor. J Med Chem. 2005; 48:5900-8
- Perzborn E, Strassburger J, Wilmen A, Pohlmann J, Roehrig S, Schlemmer KH, Straub A. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939-an oral, direct Factor Xa inhibitor. J Thromb Haemost. 2005;3:514-21
- Kubitza D, Perzborn E, Berkowitz SD. The discovery of rivaroxaban: translating preclinical assessments into clinical practice. Front Pharmacol. 2013;4:145