Solid-phase optimisation of achiral amidinobenzyl indoles as potent and selective factor Xa inhibitors

Starting from the achiral and potent factor Xa inhibitor 1, a new and flexible solid-phase optimisation strategy is described to reduce its cationic character. By replacing one positively charged side chain by a lipophilic substituent, a novel series of highly potent and selective achiral factor Xa...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2001-01, Vol.11 (2), p.227-230
Main Authors: HEINELT, Uwe, HEROK, Silke, MATTER, Hans, WILDGOOSE, Peter
Format: Article
Language:English
Subjects:
Amides - chemical synthesis
Amides - chemistry
Amides - pharmacology
Binding Sites
Biological and medical sciences
Blood. Blood coagulation. Reticuloendothelial system
Combinatorial Chemistry Techniques
Drug Design
Factor Xa Inhibitors
Humans
Indoles - chemical synthesis
Indoles - chemistry
Indoles - pharmacology
Kinetics
Medical sciences
Pharmacology. Drug treatments
Serine Proteinase Inhibitors - chemical synthesis
Serine Proteinase Inhibitors - chemistry
Serine Proteinase Inhibitors - pharmacology
Static Electricity
Structure-Activity Relationship
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Summary:Starting from the achiral and potent factor Xa inhibitor 1, a new and flexible solid-phase optimisation strategy is described to reduce its cationic character. By replacing one positively charged side chain by a lipophilic substituent, a novel series of highly potent and selective achiral factor Xa inhibitors was discovered. The identified lipophilic replacements in the S4 pocket might be valuable for other approaches towards fXa inhibitors.
ISSN:0960-894X
1464-3405
DOI:10.1016/S0960-894X(00)00631-4