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

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 8; pp. 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: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15-04-2009; Elsevier
• 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; Rat; Monkey; Coagulation Factor Xa; Anticoagulant; Selectivity; Modeling; Pyridine derivatives; Structure activity relation; Chlorine Organic compounds; Molecular model; Primates; Antithrombotic agent; Chemical synthesis; Dog; Fissipedia; Carnivora; Serine endopeptidases; Ether; Enzyme; Rodentia; Oral administration; Enzyme inhibitor; Inhibitor enzyme complex; Bioavailability; In vitro; Peptidases; In vivo; Vertebrata; Amidine; Mammalia; Animal; Hydrolases; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.02.111

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.