Design and synthesis of factor Xa inhibitors and their prodrugs

In addition to our previously reported fluoro acrylamides Xa inhibitors 2 and 3, a series of potent and novel cyclic diimide amidine compounds has been identified. In efforts to improve their oral bioavailability, replacement of the amidine group with methyl amidrazone gives compounds of moderate po...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2003-01, Vol.13 (2), p.297-300
Main Authors: Song, Yonghong, Clizbe, Lane, Bhakta, Chhaya, Teng, Willy, Wong, Paul, Huang, Brian, Tran, Katherine, Sinha, Uma, Park, Gary, Reed, Andrea, Scarborough, Robert M, Zhu, Bing-Yan
Format: Article
Language:English
Subjects:
Amidines - chemical synthesis
Amidines - pharmacology
Animals
Biological and medical sciences
Biological Availability
Blood. Blood coagulation. Reticuloendothelial system
Dogs
Drug Design
Factor Xa Inhibitors
Medical sciences
Pharmacology. Drug treatments
Prodrugs - chemical synthesis
Prodrugs - pharmacology
Rats
Serine Proteinase Inhibitors - chemical synthesis
Serine Proteinase Inhibitors - pharmacology
Structure-Activity Relationship
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Summary:In addition to our previously reported fluoro acrylamides Xa inhibitors 2 and 3, a series of potent and novel cyclic diimide amidine compounds has been identified. In efforts to improve their oral bioavailability, replacement of the amidine group with methyl amidrazone gives compounds of moderate potency ( 14, IC 50=0.028 μM). In the amidoxime prodrug approach, the amidoxime compounds show good oral bioavailability in rats and dogs. High plasma level of prodrug 26 and significant concentration of active drug 26a were obtained upon oral administration of prodrug 26 in rats. In addition to our previously reported fluoro acrylamides Xa inhibitors 2 and 3, a series of potent and novel cyclic diimide amidine compounds has been identified. In efforts to improve their oral bioavailability, replacement of the amidine group with methyl amidrazone gives compounds of moderate potency ( 14, IC 50=0.028 μM). In the amidoxime prodrug approach, the amidoxime compounds show good oral bioavailability in rats and dogs. High plasma level of prodrug 26 and significant concentration of active drug 26a were obtained upon oral administration of prodrug 26 in rats.
ISSN:0960-894X
1464-3405
DOI:10.1016/S0960-894X(02)00921-6