Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-( N, N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor

Systematic SAR studies of in vitro factor Xa inhibitory activity around compound 1 were performed by modifying each of the three phenyl rings. A class of highly potent, selective, efficacious and orally bioavailable direct factor Xa inhibitors was discovered. These compounds were screened in hERG bi...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2009-04, Vol.19 (8), p.2179-2185
Main Authors: Zhang, Penglie, Huang, Wenrong, Wang, Lingyan, Bao, Liang, Jia, Zhaozhong J., Bauer, Shawn M., Goldman, Erick A., Probst, Gary D., Song, Yonghong, Su, Ting, Fan, Jingmei, Wu, Yanhong, Li, Wenhao, Woolfrey, John, Sinha, Uma, Wong, Paul W., Edwards, Susan T., Arfsten, Ann E., Clizbe, Lane A., Kanter, James, Pandey, Anjali, Park, Gary, Hutchaleelaha, Athiwat, Lambing, Joseph L., Hollenbach, Stanley J., Scarborough, Robert M., Zhu, Bing-Yan
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Anticoagulants - administration & dosage
Anticoagulants - chemical synthesis
Anticoagulants - pharmacology
Benzamides - administration & dosage
Benzamides - chemical synthesis
Benzamides - pharmacology
Biological and medical sciences
Blood. Blood coagulation. Reticuloendothelial system
Catalytic Domain - drug effects
Cell Line
Dogs
Dose-Response Relationship, Drug
Drug Discovery - methods
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels - genetics
Factor Xa - metabolism
Factor Xa Inhibitors
Humans
Macaca fascicularis
Medical sciences
Pharmacology. Drug treatments
Pyridines - administration & dosage
Pyridines - chemical synthesis
Pyridines - pharmacology
Rabbits
Rats
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Summary:Systematic SAR studies of in vitro factor Xa inhibitory activity around compound 1 were performed by modifying each of the three phenyl rings. A class of highly potent, selective, efficacious and orally bioavailable direct factor Xa inhibitors was discovered. These compounds were screened in hERG binding assays to examine the effects of substitution groups on the hERG channel affinity. From the leading compounds, betrixaban (PRT054021) has been selected as the clinical candidate for development. Systematic SAR studies of in vitro factor Xa inhibitory activity around compound 1 were performed by modifying each of the three phenyl rings. A class of highly potent, selective, efficacious and orally bioavailable direct factor Xa inhibitors was discovered. These compounds were screened in hERG binding assays to examine the effects of substitution groups on the hERG channel affinity. From the leading compounds, betrixaban (compound 11, PRT054021) has been selected as the clinical candidate for development.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2009.02.111