N, N-Dialkylated 4-(4-arylsulfonylpiperazine-1-carbonyl)-benzamidines and 4-((4-arylsulfonyl)-2-oxo-piperazin-1-ylmethyl)-benzamidines as potent factor Xa inhibitors

A class of N,N-dialkylated 4-(4-arylsulfonylpiperazine-1-carbonyl)-benzamidines and 4-((4-arylsulfonyl)-2-oxo-piperazin-1-ylmethyl)-benzamidines has been discovered as potent factor Xa inhibitors with desirable in vitro and in vivo anticoagulant activity, but with low oral bioavailability. The 5-chl...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2004-05, Vol.14 (9), p.2073-2078
Main Authors: JIA, Zhaozhong J, TING SU, WENRONG HUANG, WOOLFREY, John, SINHA, Uma, ARFSTEN, Ann E, HUTCHALEELAHA, Athiwat, HOLLENBACH, Stanley J, LAMBING, Joseph L, SCARBOROUGH, Robert M, ZHU, Bing-Yan, ZUCKETT, Jingmei F, YANHONG WU, GOLDMAN, Erick A, WENHAO LI, PENGLIE ZHANG, CLIZBE, Lane A, YONGHONG SONG, BAUER, Shawn M
Format: Article
Language:English
Subjects:
Benzamidines - chemistry
Benzamidines - pharmacokinetics
Benzamidines - pharmacology
Biological and medical sciences
Biological Availability
Blood. Blood coagulation. Reticuloendothelial system
Factor Xa Inhibitors
Medical sciences
Pharmacology. Drug treatments
Serine Proteinase Inhibitors - chemistry
Serine Proteinase Inhibitors - pharmacokinetics
Serine Proteinase Inhibitors - pharmacology
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Summary:A class of N,N-dialkylated 4-(4-arylsulfonylpiperazine-1-carbonyl)-benzamidines and 4-((4-arylsulfonyl)-2-oxo-piperazin-1-ylmethyl)-benzamidines has been discovered as potent factor Xa inhibitors with desirable in vitro and in vivo anticoagulant activity, but with low oral bioavailability. The 5-chloroindole and 6-chlorobenzo[b]thiophene groups are optimal as the factor Xa S1 binding elements. The strategy of incorporating a side chain on the piperazine nucleus to enhance binding affinity has been examined.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2004.02.049