2018 Global Small Molecule Sales Crown - The Birth Of Apixaban

Apixaban is a direct factor Xa (factor Xa, FXa) inhibitor used as an anticoagulant to reduce the risk of stroke and systemic embolism in patients with non-valve atrial fibrillation, as well as to prevent the formation of deep vein thrombosis, DVTDeveloped by Pfizer and Bristol-Myers Squibb,BMS, Apixaban was approved by the European Drug Administration (EMA) on May 18, 2011 and then listed on December 28, 2012 Japan was approved by the U.SFood and Drug Administration (FDA) for listing, on December 25, 2012 by the Japan Pharmaceutical Medical DeviceS Agency (PMDA) approved for listing, on January 22, 2013 by the China Food and Drug Administration (CFDA) approved for listingIn just past 2018, the global drug sales champion is still the macromolecule monoantinodrug Sampero (although only a little short of $20 billion), the Top2 variety is a small molecule drug, but no longer alynadoamine, but the anticoagulant FXa inhibitor apixabanApixaban not only surpassed the first drug of the same target, levachaban, but also won the 2018 global small molecule drug sales NO.1, so the results of the industry amazed! And behind it, how this molecule gets, its process is even more exciting! 01The drug target FXa Xa factor is a protein hydrolysis enzyme in the blood cascade reaction, the function is to convert the clotting enzyme genus into clotting enzyme, its importance lies in the end of the clotting process triggered by internal mechanism or external stimulationFXa as an enzyme molecule has a magnification effect, an FXa molecule can be tens of thousands of coagulation enzymes hydrolysised and activated into coagulation enzymes, therefore, FXa inhibitors are also considered more efficient antithrombotic drugsFXa is a trypsin-like protease that directly inhibits the activity of FXa, thereby inhibiting the production of clotting enzymes and blocking thrombosis and clottingFXa does not affect platelet function, reduces the risk of bleeding, and is better than clotting enzyme inhibitors and antiplatelet aggregation drugsFigure 1In addition to the X-ray interaction between FXa and apixaban, we take a look at the first drug on the same target, LevasabanLevachaban, an oral drug developed by Bayer, was first launched in Canada and the European Union in 2008 and launched in China in 2009 for the prevention® of VTE for patients with selective hip or knee replacement surgeryStructurally, in 1998 Bayer began to develop a team of small molecule FXa inhibitors (FXa inhibitors originally derived from otters), through high-throughput screening (hundreds of thousands of levels), obtained the structure of the seed compounds, and then through a series of optimizations, and finally obtained delavsabanA further comparison of the structure of the saban and apixaban, it will be found that apixaban in the structure is definitely not a lot of traditional similar target drugs me-too, me-better, but experienced a variety of structural modification, skeleton jumping and other operations, and finally got a new type of FXa inhibitorFigure 2Deva sabelet and apixaban structural differences 02, from seed compounds to candidate compounds from seed to candidate to apixaban, this process involves a variety of principles and methods, such as skeleton jump, electronics and other rows, molecular flattening docking, etc., difficult to operate, work is complicated! The early work is the same as most drug discovery, that is, to increase activity! Preseve-aromatic compound Initially, several companies reported anti-thrombosis compounds for FXa, DuPont by screening the IIb/IIIa receptor antagonists (the company has studied in depth) on the activity of FXa, found that the following compounds on FXa's Ki value of 38.5 smolL-1, but the structure is monoto-aromatic compoundsFigure 3The single-aromatic structure obtained by the general sieve, the single-aromatic structure, the double-aromatic structure at the time, the double-aromatic structure was the mainstream structure, by replacing the right tetrahydrohexythyl butyric acid fragment with benzene, while further examining the compound's effect on coagulation enzymes (stronger as possible) and trypenems (the weaker the better) to explore selective activityFigure 4The evolution of the mono-aromatic to double-aromatic structure, the double-aromatic structure and the isothium ring, replaced by reducing molecular flexibility, removing the methyl between the isovanaring ring and the amide, and introducing a side chain containing the base of the isothazole ring, but there was no breakthroughFigure 5The introduction of the bi-aromatic structure containing the base side chain, the biphenyl structure, the double-aromatic structure was changed to biphenyls, and it was found that the combination cavity S4 of biphenyls and FXa was a hydrophobic cavity composed of amino acid residues such as Trp215, Tyr99 and Phe174The binding characteristics of molecular simulation and FXa show that the oxygen atoms of sulfonyl are highly hydrogen bonded with Tyr99 and highly selectiveFigure 6The introduction of biphenyls biphenyl fragments and near-end benzene ring optimization and side-chain ester base transformation fixed inter-bit argon-based, isting ring of acetate, to investigate the effect of the intermediate aromatic ring on the activity; Figure 7Near-end benzene ring optimization and side-chain ester-based transformation isniotic ring, hetero-pyridine ring is not aromatic ring, contains hand carbon atoms, and proves that the 5-bit carbon chain has little effect on the activity, and then replaces isotriate with pyreth, the activity is not changed, and at the same time convenient synthesisAfter the optimization of the radon structure as a new starting point (IC50 has reached 0.13 nM)Figure 8The introduction of pyridine-CH3 s-CF3- active-selective 3-methyl-replaced pyreth compounds increased the inhibition of FXa by an order of magnitude, and the pyregas replaced by 3-trofluoromethyl, with greater activityMost compounds have a lower removal-rate distribution volume and a longer half-life, but oral bioavailability is less than 5%, which does not meet the requirements for oral administrationMolecular structure contains a strong alkaline conicyl (pKa is 10.7), in the body molecules with a positive charge, not easy to over-membrane absorption, and therefore oral absorption differenceSome compoundPK/PD data are as follows Figure 9 From the activity extended to more pharmaceutical properties 03, the candidate compound of the determination of DPC-423 pyrehyleta instead of benzene structure, the activity is slightly weaker than the pyridine compound 1-2 orders of magnitude, but because the pyridine base has a high level of pM activity, can withstand the reduction of activity, to make up for the absorption of overfilm, optimize the total effect of the drug replacement By reducing the alkalinity of the molecule, the absorption of the membrane is increased In the cesium compounds, the pyrolyse ring has the replacement of trifluoromethyl, the near end of the biphenyls replaced by fluorine, the far end benzene ring 4-methyl sulfosium-replacement compounds the best oral bioavailability, half-life of 7.5 h, with the rabbit vein shuntthrombosis model determined ID50 L-1 To give these active data and pharmacokinetic properties, DuPont identified the candidate compound, numberEd DPC-423, for development Figure 10 DPC-423 chemical structure Reza saban structural relationship research shows that: DPC-423 methicillin base converted into ammonia sulfose, its activity is not changed, selective increase, but the transfilmability is significantly reduced, due to increased molecular polarity; Increased hyperfilm, but therefore with plasma protein binding rate of 97%, is also the reason for reduced activity; Figure 11 Reza Saban chemical structure BMS740808 Taking into account that the amide bonds may be hydrolyzed in the body into pyrethronic acid and congoamine, the latter has the risk of potential mutation, so it is necessary to avoid the toxic alert structure, based on the principle of minimum structural transformation, the amidamide ring to the ring, form and combine the heterocyclic structure to improve metabolic stability The combination of rezasaban's amino benzene and hexazole and heterocyclic cyclium, the synthesis of a new class of compounds, the structural relationship is summarized as follows: (1) transformation of the far-end benzene ring on the serotonin base, metformin methyl and 3-R-hydroxytetrahydroxythinactivity is the strongest, the body anti-coagulation effect is also the strongest (2) The aphorous atoms are introduced in the adjacent phase of the near-end benzene ring, which is weaker than the corresponding compound activity (3) 3-hydroxy tetrahydroxydium R configuration activity is 3 times stronger than its S configuration, and the anticoagulant activity in the body is also stronger than the S-type (4) The trifluoromethyl on the radon ring is replaced by methyl, and the activity is reduced Pharmacokinetic studies of bigethnosis show that the following compounds have the best properties, namely BMS 740808 Figure 12 BMS740808 Chemical Structure 04, the birth of apixaban candidates are compounds DPC423, Reza Saban, BMS740808, the next step is to further optimize these fragments from in vitro FXa activity, selectivity, in vivo anticoagulants and pharmaceutical properties and other multi-dimensional optimization to determine better structure The advantages of benzodiazepine, pyrithione and dihydroquine, biphenylsamines and other advantages were stitched together to transform the replacement base on the pyrethroamine ring and synthesize a series of compounds Among them, compounds such as methyl sulfonyl, amino, cyanide and tetrapyrifos have higher activity and selectivity compared with serfluoromethyl compounds, and the anticoagulant effect in the body is significantly stronger than BMS740808, suggesting that these groups can be transplanted on different mother cores Relatively comparison, the resulting compound has good pharmacokinetic properties, low removal rate (CL 0.32L.kg?1?h-1), half-life t1/2 is 5.6 h, oral bioavailability F is 100%, so the amino fixed, further optimized Figure 13 Fixed of the structure of ampereinininininininium is in the above-mentioned structural optimization, another simultaneous study is to explore the transformation of the distant end benzene ring replacement base on the activity effect, found that the single benzene ring of the position N-methylacetamite replacement is unique, because free ammonia or other related group activity is very poor, suggesting that the amide should be an important group involved in the binding The determination of the replacement and candidate of the paracetamol corrected the fat solubility of trifluoromethyl, combined with the far-end benzene ring-to-position N-methyl acetaminophen replaced, the following compounds, in vitro inhibition of FXa and in vivo anticoagulant effectands and selectivity are very strong The activity of protease and liver CYP in human serotonin is very weak, such as the half-life of the end-end benzene ring containing endamide structure compounds and liver particle body temperature incubation of 100 min, Caco-2 cells are also very high membraneation, plasma protein binding rate of 87%, home rabbit anti-thrombosis IC50 s 329 nmol L-1, oral half-life of 5.8 h, oral bioavailability F-58% Finally, our small molecular drug king Apixaban, was born! Figure 14 Apixaban was finally born 05, the knot Apixaban molecular structure design process, can be said to be excellence! In the early acquisition of a number of very active very very good compounds, not ventured, eager to develop, but continue to study the activity, with a view to the subsequent medicinal structural transformation to lay a sufficient amount of sacrificial activity! The principle and method of structural transformation seem to be broad-spectrum, but it actually shows a very good degree of organic combination, especially the skeleton structure spanning the delavaban and the double-twisted structure of the early seed compound, this bold abandonment of the "classic structure" of the development of domestic drug molecules is very instructive Reference: 1 Design and synthesis of isoxazolines as factor Xa a J Med Chem.1999 DOI: 10.1021/jm980406a 2 Discovery of 1 - (aminomme) phenyl-N- (3-fluoro-2' - (methylsulfonyl) - 1'-biphenyl- 4-yl- - 3-(trifluoromethyl) - 1H-pyrazole-5-car-carmenente (DPC423), a selective, and orally bioavailable put of the blood coagulation factor Xa 2001 DOI: 10.1016/S0030-4018 (98)00117-5 3 Structure-based design of novel guanidine/benzamidineeephotos: potent and or bioavailable factor Xa catas as novel anticoagulants 2003 DOI: 10.1021/jm020578e 4 Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxoberidin-1-yl) phenyl-4,5,6-7-tetrahydro-1H-pyrazolo 3,4-c-pyridine-3-carboxamide (Apixaban, BMS-562247), a highly potent, selective, eicean, and orori bioavailable of the blood coagulation factor Xa 2007 DOI: org/10.1021/jm070245n 5 Discovery of the potent, efficacious, and orallybioavailables of the blood coagulation factor Xa with neutral P1 moieis DOI: 10.1016/j.bmcl.2006.08.027 6 Multi-dimensional optimization created by Apixaban Guo Zongju 7 The current situation and application of the direct inhibitor of coagulation factor Xa 2018.