Polymer-Assisted solution-Phase (PASP) parallel synthesis of an α-Ketothiazole library as tissue factor VIIa inhibitors

A solution-phase synthesis of an α-ketothiazole library of the general form d-Phe- l-AA- l-Arg-α-ketothiazole is described. The five-step synthesis is accomplished using a combination of polymeric reagents and polymer-assisted solution-phase purification protocols, including reactant-sequestering re...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2003-07, Vol.13 (14), p.2363-2367
Main Authors: South, Michael S, Dice, Thomas A, Girard, Thomas J, Lachance, Rhonda M, Stevens, Anna M, Stegeman, Roderick A, Stallings, William C, Kurumbail, Ravi G, Parlow, John J
Format: Article
Language:English
Subjects:
Anticoagulants - chemical synthesis
Anticoagulants - pharmacology
Biological and medical sciences
Blood. Blood coagulation. Reticuloendothelial system
Crystallography, X-Ray
Factor VIIa - antagonists & inhibitors
Factor Xa Inhibitors
Humans
Indicators and Reagents
Medical sciences
Models, Molecular
Pharmacology. Drug treatments
Structure-Activity Relationship
Thiazoles - chemical synthesis
Thiazoles - pharmacology
Thrombin - antagonists & inhibitors
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Summary:A solution-phase synthesis of an α-ketothiazole library of the general form d-Phe- l-AA- l-Arg-α-ketothiazole is described. The five-step synthesis is accomplished using a combination of polymeric reagents and polymer-assisted solution-phase purification protocols, including reactant-sequestering resins, reagent-sequestering resins, and tagged reagents. The multi-step synthesis affords the desired α-ketothiazole products in excellent purities and yields. A variety of l-amino acid inputs were used to probe the S2 pocket of the tissue factor (TF) VIIa enzyme to influence both potency and selectivity. An X-ray crystal structure of compound 10e bound to the TF/VIIa complex was obtained that explains the observed selectivity. The α-ketothiazoles were found to be potent, reversible-covalent inhibitors of tissue factor VIIa, with some analogues demonstrating selectivity versus thrombin. A solution phase library synthesis of 10 is described. An X-ray crystal structure of the sub-micromolar inhibitors with the TF/VIIa enzyme explains the observed selectivity versus thrombin.
ISSN:0960-894X
1464-3405
DOI:10.1016/S0960-894X(03)00398-6