2P16

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

2P16 の概要

• エントリーDOI: 10.2210/pdb2p16/pdb
• 分子名称: Coagulation factor X (EC 3.4.21.6) (Stuart factor) (Stuart-Prower factor), CALCIUM ION, 1-(4-METHOXYPHENYL)-7-OXO-6-[4-(2-OXOPIPERIDIN-1-YL)PHENYL]-4,5,6,7-TETRAHYDRO-1H-PYRAZOLO[3,4-C]PYRIDINE-3-CARBOXAMIDE, ... (5 entities in total)
• 機能のキーワード: glycoprotein, hydrolase, serine protease, plasma, blood coagulation factor, protein inhibitor complex, calcium-binding
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Secreted: P00742 P00742
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 32535.91

構造登録者

Alexander, R. (登録日: 2007-03-02, 公開日: 2007-10-16, 最終更新日: 2024-10-09)

主引用文献

Pinto, D.J.,Orwat, M.J.,Koch, S.,Rossi, K.A.,Alexander, R.S.,Smallwood, A.,Wong, P.C.,Rendina, A.R.,Luettgen, J.M.,Knabb, R.M.,He, K.,Xin, B.,Wexler, R.R.,Lam, P.Y.
Discovery of 1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro- 1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Apixaban, BMS-562247), a Highly Potent, Selective, Efficacious, and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa.
J.Med.Chem., 50:5339-5356, 2007

PubMed Abstract: 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-tetrahydro-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.

PubMed: 17914785
DOI: 10.1021/jm070245n

実験手法

X-RAY DIFFRACTION (2.3 Å)