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.
Publication type: Journal Article
Publication date: 2007-10-03
scimago Q1
wos Q1
SJR: 1.801
CiteScore: 11.5
Impact factor: 6.8
ISSN: 00222623, 15204804
PubMed ID:
17914785
Drug Discovery
Molecular Medicine
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.
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360
Total citations:
360
Citations from 2024:
24
(6.67%)
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Pinto D. J. et al. 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. // Journal of Medicinal Chemistry. 2007. Vol. 50. No. 22. pp. 5339-5356.
GOST all authors (up to 50)
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Pinto D. J., Orwat M. J., Koch S., Rossi K. A., Alexander R. S., Smallwood A., Wong P. C., RENDINA A., Luettgen J. M., Knabb R. M., He K., Xin B., Wexler R. R., Lam P. Y. S. 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. // Journal of Medicinal Chemistry. 2007. Vol. 50. No. 22. pp. 5339-5356.
Cite this
RIS
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TY - JOUR
DO - 10.1021/jm070245n
UR - https://doi.org/10.1021/jm070245n
TI - 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.
T2 - Journal of Medicinal Chemistry
AU - Pinto, Donald J
AU - Orwat, Michael J.
AU - Koch, Stephanie
AU - Rossi, Karen A.
AU - Alexander, Richard S.
AU - Smallwood, Angela
AU - Wong, Pancras C.
AU - RENDINA, Alan R.
AU - Luettgen, Joseph M.
AU - Knabb, Robert M.
AU - He, Kan
AU - Xin, Baomin
AU - Wexler, Ruth R.
AU - Lam, Patrick Y S
PY - 2007
DA - 2007/10/03
PB - American Chemical Society (ACS)
SP - 5339-5356
IS - 22
VL - 50
PMID - 17914785
SN - 0022-2623
SN - 1520-4804
ER -
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@article{2007_Pinto,
author = {Donald J Pinto and Michael J. Orwat and Stephanie Koch and Karen A. Rossi and Richard S. Alexander and Angela Smallwood and Pancras C. Wong and Alan R. RENDINA and Joseph M. Luettgen and Robert M. Knabb and Kan He and Baomin Xin and Ruth R. Wexler and Patrick Y S Lam},
title = {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.},
journal = {Journal of Medicinal Chemistry},
year = {2007},
volume = {50},
publisher = {American Chemical Society (ACS)},
month = {oct},
url = {https://doi.org/10.1021/jm070245n},
number = {22},
pages = {5339--5356},
doi = {10.1021/jm070245n}
}
Cite this
MLA
Copy
Pinto, Donald J., et al. “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..” Journal of Medicinal Chemistry, vol. 50, no. 22, Oct. 2007, pp. 5339-5356. https://doi.org/10.1021/jm070245n.