1,2-Disubstituted cyclohexane derived tripeptide aldehydes as novel selective thrombin inhibitors

A series of tripeptide arginine aldehydes was synthesized by replacement of proline with 1,2-disubstituted cyclohexane derivatives in the sequence of D-MePhe-Pro-Arg-H. Based on molecular modeling, further modification of the D-MePhe residue resulted in a potent and selective thrombin inhibitor. Two...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 1998-05, Vol.8 (10), p.1249-1254
Main Authors: Harmat, Nicholas J.S., Di Bugno, Cristina, Criscuoli, M., Giorgi, Raffaello, Lippi, Annalisa, Martinelli, Adriano, Monti, Susanna, Subissi, A.
Format: Article
Language:English
Subjects:
Aldehydes
Amino Acid Sequence
Antithrombins - chemical synthesis
Antithrombins - chemistry
Antithrombins - pharmacology
Arginine
Binding Sites
Biological and medical sciences
Blood. Blood coagulation. Reticuloendothelial system
Cyclohexanes - chemical synthesis
Cyclohexanes - chemistry
Cyclohexanes - pharmacology
Indicators and Reagents
Kinetics
Medical sciences
Models, Molecular
Molecular Structure
Oligopeptides - chemical synthesis
Oligopeptides - chemistry
Oligopeptides - pharmacology
Pharmacology. Drug treatments
Protein Conformation
Stereoisomerism
Structure-Activity Relationship
Thrombin - metabolism
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Summary:A series of tripeptide arginine aldehydes was synthesized by replacement of proline with 1,2-disubstituted cyclohexane derivatives in the sequence of D-MePhe-Pro-Arg-H. Based on molecular modeling, further modification of the D-MePhe residue resulted in a potent and selective thrombin inhibitor. Two series of tripeptide arginine aldehydes Ph(CH 2) nNH(Me)-1,2-COcC 6H 10COArgH and D-MePhe-1,2-(CONH)cC 6H 10COArgH bearing a central 1,2-disubstituted cyclohexane moiety of defined stereochemistry were synthesized and screened for thrombin inhibition activity. Later modification of the aromatic side chain in the light of modeling studies led to the potent and selective inhibitor 13e.
ISSN:0960-894X
1464-3405
DOI:10.1016/S0960-894X(98)00200-5