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partment, the pharmacokineticprofile of these agents would also feature a low volume ofdistributionand mk2206 low systemicclearance.Based on numerous years of study and development, wehave identified the potent, highly selective and direct FXainhibitor, apixaban. Apixaban isone of 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 within the prevention and treatmentof various thromboembolic illnesses. The pharmacologicaland clinical profiles of apixaban suggest that ithas the potential to address numerous of the limitations ofwarfarin therapy, at present the standard of care in chronicoral anticoagulation.
In this assessment, we summarize thechemistry and pre-clinical profile of apixaban.ChemistryApixaban is actually 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 within the development of inhibitors of glycoproteinIIb/IIIa. These efforts resulted in several compoundsthat had been advanced to clinical trials as potentialanti-platelet agents. By the mid-1990s, scientists at DuPonthad recognized similarities 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 within the AP26113 identificationof a little number of isoxazoline derivatives for example 1. Employing molecular modelingand structure-based style, an optimization strategyresulted within 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 developed to neatly stackin the S4 hydrophobic box of FXa, which consists of theresidues Tyr99, Phe174 and Trp215, with all the terminalO-phenylsulfonamide ring creating an edge-to-face interactionwith Trp215.
Subsequent re-optimizations led tovicinally substituted isoxazole analogs for example compound3, which retained anti-FXa potencyand AP26113 a pyrazole analog 4, which demonstrated13 pM binding affinity against FXa and excellent antithromboticactivity inside a rabbit model of thrombosis. Thediscovery of SN429 was tremendously important in that itset the stage for an optimization approach that led to thediscovery of several important compounds, for example 5, a phase I clinical candidate with a lengthy terminalhalf-life of around 30 h in humans, and 6, a compound that was advanced to aphase II proof-of-principle clinical trial. In reality, razaxabanwas the very first little molecule FXa inhibitor to provideclinical validation of the effectiveness of FXa inhibitionstrategies.Development of razaxaban was promptly followed by theidentification of a novel bicyclic tetrahydropyrazolo-pyridinoneanalog 7.
The evolution of 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 excellent 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 and also a carboxamidopyrazole moiety, that led towards the discovery of 9, a highly potent andselective FXa inhibitor with excellent efficacy in various 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 fast 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 is actually a highly potent, reversible, active-site inhibitorof human FXa, with a Ki of 0.08 nM at 25*C and 0.25 nMat 37*C within 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 within the active website. Apixaban producesa fast onset of inhibition below a variety of 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