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partment, the pharmacokineticprofile of these agents would also feature a low volume ofdistributionand low systemicclearance.According to quite a few years of analysis and development, wehave identified the potent, very selective and direct FXainhibitor, apixaban. Letrozole Apixaban isone with the most promising particular, 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 different thromboembolic diseases. The pharmacologicaland clinical profiles of apixaban suggest that ithas the possible to address quite a few with the limitations ofwarfarin therapy, presently the common of care in chronicoral anticoagulation.
Letrozole In this assessment, 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. 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 numerous compoundsthat had been advanced to clinical trials as potentialanti-platelet agents. By the mid-1990s, scientists at DuPonthad recognized similarities amongst the platelet glycoproteinGPIIb/IIIa peptide sequence Arg-Gly-Aspandthe prothrombin substrate FXa sequence, Glu-Gly-Arg.
Consequently, a high-throughput mapk inhibitor lead evaluationprogram was initiated to screen the IIb/IIIa library for FXainhibitory activity. This effort resulted in the identificationof a tiny number of isoxazoline derivatives including 1. Utilizing molecular modelingand structure-based style, an optimization strategyresulted in the identification of a benzamidine containingFXa inhibitor 2with enhanced potencyand potent antithrombotic activity in anexperimental model of thrombosis. Aside from thekey amidine P1 and the enzyme Asp189 interaction, thebiarylsulfonamide P4 moiety was developed to neatly stackin the S4 hydrophobic box of FXa, which contains theresidues Tyr99, Phe174 and Trp215, with the terminalO-phenylsulfonamide ring producing an edge-to-face interactionwith Trp215.
Subsequent re-optimizations led tovicinally substituted isoxazole analogs including compound3, which retained anti-FXa potencyand a pyrazole analog 4, which demonstrated13 pM binding affinity against FXa and very good antithromboticactivity in a rabbit model of thrombosis. Thediscovery of SN429 was tremendously critical NSCLC in that mapk inhibitor itset the stage for an optimization strategy that led to thediscovery of numerous critical compounds, including 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 reality, razaxabanwas the first tiny molecule FXa inhibitor to provideclinical validation with the effectiveness of FXa inhibitionstrategies.Development of razaxaban was swiftly followed by theidentification of a novel bicyclic tetrahydropyrazolo-pyridinoneanalog 7.
The evolution with the bicyclic pyrazole template allowed forthe incorporation of a diverse set of P1 groups, the mostimportant of which was the p-methoxyphenyl analog 8. Compound 8 retained Letrozole potent FXaaffinity and very good 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 a carboxamidopyrazole moiety, that led towards the discovery of 9, a very potent andselective FXa inhibitor with very good efficacy in different animalmodels of thrombosis. Importantly, compound 9 alsoshowed an excellent pharmacokinetic profile in dogs, withlow clearance, low volume of distribution and high oralbioavailability.
The superior pre-clinical profile demonstratedby mapk inhibitor 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 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 website. Apixaban producesa rapid onset of inhibition below a range of conditionswith association rate continuous of 20of 1.3 nM. Insummary, apixaban is capable of inhibiting the activity offree FXa, thrombus-associated FXa and FXa within theprothrombinase complex. Apixaban