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partment, the pharmacokineticprofile of these agents would also feature a low volume ofdistributionand mk2206 low systemicclearance.Based on several years of research and development, wehave identified the potent, very selective and direct FXainhibitor, apixaban. Apixaban isone with the most promising specific, single-target oralanticoagulants in late clinical development. In clinical trials,apixaban has been shown to provide predictable andconsistent anticoagulation, accompanied by promisingefficacy and safety profiles in the prevention and treatmentof numerous thromboembolic diseases. The pharmacologicaland clinical profiles of apixaban suggest that ithas the potential to address several with the limitations ofwarfarin therapy, currently the regular of care in chronicoral anticoagulation.
In this evaluation, we summarize thechemistry and pre-clinical profile of apixaban.ChemistryApixaban can be a small-molecule, selective FXa inhibitor. It ischemically described as 1--7-oxo-6--4,5,6,7-tetrahydro-1H-pyrazolopyridine-3-carboxamide. mk2206 The molecular formulafor apixaban is C25H25N5O4, which corresponds to amolecular weight of 459.5.Discovery of apixabanIn the early 1990s, DuPont scientists invested a greatamount of effort in the development of inhibitors of glycoproteinIIb/IIIa. These efforts resulted in various compoundsthat had been advanced to clinical trials as potentialanti-platelet agents. By the mid-1990s, scientists at DuPonthad recognized similarities in between the platelet glycoproteinGPIIb/IIIa peptide sequence Arg-Gly-Aspandthe prothrombin substrate FXa sequence, Glu-Gly-Arg.
Consequently, a high-throughput lead evaluationprogram was initiated to screen the IIb/IIIa library for FXainhibitory activity. This effort resulted in the AP26113 identificationof a little number of isoxazoline derivatives like 1. Employing molecular modelingand structure-based design, an optimization strategyresulted in the identification of a benzamidine containingFXa inhibitor 2with enhanced NSCLC potencyand potent antithrombotic activity in anexperimental model of thrombosis. Aside from thekey amidine P1 as well as the enzyme Asp189 interaction, thebiarylsulfonamide P4 moiety was designed to neatly stackin the S4 hydrophobic box of FXa, which consists of theresidues Tyr99, Phe174 and Trp215, with all the terminalO-phenylsulfonamide ring making an edge-to-face interactionwith Trp215.
Subsequent re-optimizations led tovicinally substituted isoxazole analogs like compound3, which retained anti-FXa potencyand AP26113 a pyrazole analog 4, which demonstrated13 pM binding affinity against FXa and fantastic antithromboticactivity inside a rabbit model of thrombosis. Thediscovery of SN429 was tremendously essential in that itset the stage for an optimization approach that led to thediscovery of various essential compounds, like 5, a phase I clinical candidate having a long terminalhalf-life of roughly 30 h in humans, and 6, a compound that was advanced to aphase II proof-of-principle clinical trial. In fact, razaxabanwas the very first little molecule FXa inhibitor to provideclinical validation with the effectiveness of FXa inhibitionstrategies.Development of razaxaban was quickly followed by theidentification of a novel bicyclic tetrahydropyrazolo-pyridinoneanalog 7.
The evolution with the bicyclic pyrazole mk2206 template allowed forthe incorporation of a diverse set of P1 groups, the mostimportant of which was the p-methoxyphenyl analog 8. Compound 8 retained potent FXaaffinity and fantastic anticoagulant activity in vitro, was efficaciousin in vivo rabbit antithrombotic models andshowed high oral bioavailability in dogs. A significantbreakthrough was subsequently achieved, by way of the incorporationof a pendent P4 lactam group along with a carboxamidopyrazole moiety, that led towards the discovery of 9, a very potent andselective FXa inhibitor with fantastic efficacy in numerous animalmodels of thrombosis. Importantly, compound 9 alsoshowed a superb pharmacokinetic profile in dogs, withlow clearance, low volume of distribution and high oralbioavailability.
The superior pre-clinical profile AP26113 demonstratedby 9 enabled its rapid progression into clinicaldevelopment as apixaban. Figure 2 illustrates theX-ray structure of apixaban bound to FXa and shows thep-methoxyphenyl P1 deeply inserted into the S1 pocket,with all the aryllactam P4 moiety neatly stacked in thehydrophobic S4 pocket.In vitro pharmacologyPotency, selectivity and kinetic mode of inhibitionApixaban can be a very potent, reversible, active-site inhibitorof human FXa, having a Ki of 0.08 nM at 25*C and 0.25 nMat 37*C in the FXa tripeptide substrateassay. Analysis ofenzyme kinetics shows that apixaban acts as a competitiveinhibitor of FXa versus the synthetic tripeptide substrate,indicating that it binds in the active internet site. Apixaban producesa rapid onset of inhibition below many different conditionswith association rate constant of 20of 1.3 nM. Insummary, apixaban is capable of inhibiting the activity offree FXa, thrombus-associated FXa and FXa within theprothrombinase complex. Apixaban