Based on a lot of many years of study and development, we have now recognized the potent, remarkably selective and direct FXa inhibitor, apixaban . Apixaban is amongst the most promising unique, single-target oral anticoagulants in late clinical advancement. In clinical trials, apixaban continues to be shown to provide predictable and consistent anticoagulation, accompanied by promising efficacy and safety profiles within the prevention and remedy of many thromboembolic conditions . The pharmacological and clinical profiles of apixaban recommend that it has the possible to address lots of the limitations of warfarin treatment, at the moment the traditional of care in persistent oral anticoagulation. Within this examine, we summarize the chemistry and pre-clinical profile of apixaban. Chemistry Apixaban is a small-molecule, selective FXa inhibitor.
It truly is chemically described as 1- -7-oxo-6- -4,five,6,7-tetrahydro-1H-pyrazolo pyridine-3-carboxamide. The molecular formula for apixaban is C25H25N5O4, which corresponds to a molecular Rapamycin weight of 459.five. Discovery of apixaban Within the early 1990s, DuPont scientists invested an excellent level of work from the improvement of inhibitors of glycoprotein IIb/IIIa. These efforts resulted in many compounds that have been superior to clinical trials as likely anti-platelet agents. From the mid-1990s, scientists at DuPont had acknowledged similarities concerning the platelet glycoprotein GPIIb/IIIa peptide sequence Arg-Gly-Asp and also the prothrombin substrate FXa sequence, Glu-Gly-Arg . Consequently, a high-throughput lead evaluation system was initiated to screen the IIb/IIIa library for FXa inhibitory activity.
This hard work resulted within the identification of the compact number of isoxazoline derivatives this kind of as 1 . Applying molecular modeling and structure-based design and style, an optimization strategy resulted in the identification of the benzamidine containing FXa inhibitor 2 with enhanced potency and potent antithrombotic activity in an experimental model of thrombosis . Apart from the key amidine STAT5 inhibitor P1 plus the enzyme Asp189 interaction, the biarylsulfonamide P4 moiety was built to neatly stack in the S4 hydrophobic box of FXa, which incorporates the residues Tyr99, Phe174 and Trp215, with the terminal O-phenylsulfonamide ring producing an edge-to-face interaction with Trp215.
Subsequent re-optimizations led to vicinally substituted isoxazole analogs this kind of as compound three, which retained anti-FXa potency as well as a pyrazole analog four , which demonstrated 13 pM binding affinity towards FXa and beneficial antithrombotic exercise in a rabbit model of thrombosis . The discovery of SN429 was tremendously necessary in that it set the stage for an optimization method that led on the discovery of various essential compounds, this kind of as five , a phase I clinical candidate having a prolonged terminal half-life of somewhere around 30 h in humans , and six , a compound that was advanced to a phase II proof-of-principle clinical trial.