2p16: Difference between revisions
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New page: left|200px<br /> <applet load="2p16" size="450" color="white" frame="true" align="right" spinBox="true" caption="2p16, resolution 2.30Å" /> '''Factor Xa in Comple... |
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[[Image:2p16.gif|left|200px]]<br /> | [[Image:2p16.gif|left|200px]]<br /><applet load="2p16" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="2p16, resolution 2.30Å" /> | caption="2p16, resolution 2.30Å" /> | ||
'''Factor Xa in Complex with the Inhibitor APIXABAN (BMS-562247) AKA 1-(4-METHOXYPHENYL)-7-OXO-6-(4-(2-OXO-1-PIPERIDINYL)PHENYL)-4,5,6,7-TETRAHYDRO-1H-PYRAZOLO[3, 4-C]PYRIDINE-3-CARBOXAMIDE'''<br /> | '''Factor Xa in Complex with the Inhibitor APIXABAN (BMS-562247) AKA 1-(4-METHOXYPHENYL)-7-OXO-6-(4-(2-OXO-1-PIPERIDINYL)PHENYL)-4,5,6,7-TETRAHYDRO-1H-PYRAZOLO[3, 4-C]PYRIDINE-3-CARBOXAMIDE'''<br /> | ||
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==Overview== | ==Overview== | ||
Efforts to identify a suitable follow-on compound to razaxaban (compound, 4) focused on modification of the carboxamido linker to eliminate, potential in vivo hydrolysis to a primary aniline. Cyclization of the, carboxamido linker to the novel bicyclic tetrahydropyrazolopyridinone, scaffold retained the potent fXa binding activity. Exceptional potency of, the series prompted an investigation of the neutral P1 moieties that, resulted in the identification of the p-methoxyphenyl P1, which retained, factor Xa binding affinity and good oral bioavailability. Further, optimization of the C-3 pyrazole position and replacement of the terminal, P4 ring with a neutral heterocycle culminated in the discovery of, 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrah, ydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, compound 40)., Compound 40 exhibits a high degree of fXa potency, selectivity, and, efficacy and has an improved pharmacokinetic profile relative to 4. | Efforts to identify a suitable follow-on compound to razaxaban (compound, 4) focused on modification of the carboxamido linker to eliminate, potential in vivo hydrolysis to a primary aniline. Cyclization of the, carboxamido linker to the novel bicyclic tetrahydropyrazolopyridinone, scaffold retained the potent fXa binding activity. Exceptional potency of, the series prompted an investigation of the neutral P1 moieties that, resulted in the identification of the p-methoxyphenyl P1, which retained, factor Xa binding affinity and good oral bioavailability. Further, optimization of the C-3 pyrazole position and replacement of the terminal, P4 ring with a neutral heterocycle culminated in the discovery of, 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrah, ydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, compound 40)., Compound 40 exhibits a high degree of fXa potency, selectivity, and, efficacy and has an improved pharmacokinetic profile relative to 4. | ||
==About this Structure== | ==About this Structure== | ||
2P16 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with CA and GG2 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Coagulation_factor_Xa Coagulation factor Xa], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.6 3.4.21.6] Full crystallographic information is available from [http:// | 2P16 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=CA:'>CA</scene> and <scene name='pdbligand=GG2:'>GG2</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Coagulation_factor_Xa Coagulation factor Xa], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.6 3.4.21.6] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2P16 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: serine protease]] | [[Category: serine protease]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 12:12:36 2008'' | ||
