The design and synthesis of thrombin inhibitors: analogues of MD805 containing non-polar surrogates for arginine at the P1 position

A series of monocyclic and bicyclic amino acids have been synthesised and incorporated into thrombin inhibitors based on CGH728, an analogue of the Mitsubishi compound MD805. Benzthiazolylalanine (Bta) was found to be a good non-polar substitute for arginine at the P1 position, yielding compounds wi...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2000-07, Vol.10 (14), p.1563-1566
Main Authors: Baettig, Urs, Brown, Lyndon, Brundish, Derek, Dell, Colin, Furzer, Alex, Garman, Sheila, Janus, Diana, Kane, Peter D, Smith, Garrick, Walker, Clive V, Cockcroft, Xiaoling, Ambler, John, Mitchelson, Andrew, Talbot, Mark D, Tweed, Morris, Wills, Nicholas
Format: Article
Language:English
Subjects:
Alanine
Antithrombins - chemical synthesis
Antithrombins - chemistry
Antithrombins - pharmacology
Arginine
Biological and medical sciences
Blood. Blood coagulation. Reticuloendothelial system
Chymotrypsin - antagonists & inhibitors
Drug Design
Factor Xa Inhibitors
Fibrinolysin - antagonists & inhibitors
Kallikreins - antagonists & inhibitors
Medical sciences
Models, Molecular
Molecular Structure
Pharmacology. Drug treatments
Pipecolic Acids - chemical synthesis
Pipecolic Acids - chemistry
Pipecolic Acids - pharmacology
Serine Proteinase Inhibitors - chemical synthesis
Serine Proteinase Inhibitors - chemistry
Serine Proteinase Inhibitors - pharmacology
Structure-Activity Relationship
Thiazoles
Thrombin - metabolism
Trypsin - metabolism
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Summary:A series of monocyclic and bicyclic amino acids have been synthesised and incorporated into thrombin inhibitors based on CGH728, an analogue of the Mitsubishi compound MD805. Benzthiazolylalanine (Bta) was found to be a good non-polar substitute for arginine at the P1 position, yielding compounds with low nanomolar potency and good selectivity for thrombin.
ISSN:0960-894X
1464-3405
DOI:10.1016/S0960-894X(00)00282-1