the design and synthesis of thrombin inhibitors: the introduction of in vivo efficacy and oral bioavailability into benzthiazolylalanine inhibitors

The further optimisation of the novel lead compound CGH752 (Fig. 1) is described. By introducing various substituents into the 6-position of the 3,3-dimethyltetrahydroquinoline (DMTHQS) ring we have been able to favourably affect the in vitro and in vivo activity, and the pharmacokinetics of such co...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2000-07, Vol.10 (14), p.1567-1570
Main Authors: Hayler, Judy, Kane, Peter D, LeGrand, Darren, Lugrin, Florence, Menear, Keith, Price, Richard, Allen, Mark, Cockcroft, Xiaoling, Ambler, John, Butler, Keith, Dunnet, Karren, Mitchelson, Andrew, Talbot, Mark, Tweed, Morris, Wills, Nicholas
Format: Article
Language:English
Subjects:
Administration, Oral
Alanine - analogs & derivatives
Alanine - chemical synthesis
Alanine - chemistry
Alanine - pharmacokinetics
Animals
Antithrombins - chemical synthesis
Antithrombins - chemistry
Antithrombins - pharmacokinetics
Biological and medical sciences
Biological Availability
Blood. Blood coagulation. Reticuloendothelial system
Chymotrypsin - antagonists & inhibitors
Drug Design
Fibrinolysin - antagonists & inhibitors
Kinetics
Medical sciences
Molecular Conformation
Molecular Structure
Partial Thromboplastin Time
Pharmacology. Drug treatments
Structure-Activity Relationship
Sulfonamides - chemistry
Sulfonamides - pharmacokinetics
Thiazoles - chemistry
Thiazoles - pharmacokinetics
Thrombosis - drug therapy
Trypsin - metabolism
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Summary:The further optimisation of the novel lead compound CGH752 (Fig. 1) is described. By introducing various substituents into the 6-position of the 3,3-dimethyltetrahydroquinoline (DMTHQS) ring we have been able to favourably affect the in vitro and in vivo activity, and the pharmacokinetics of such compounds. One of the inhibitors synthesised (CGH1484) is bioavailable and shows efficacy in animal models of thrombosis.
ISSN:0960-894X
1464-3405
DOI:10.1016/S0960-894X(00)00283-3