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New thrombin inhibitors based on D-cha-Pro-derivatives.
T Steinmetzer1, M Batdorsdhjin, P Kleinwächter
1Inst. of Biochemistry & Biophysics, Friedrich Schiller University, Jena, Germany. steinmetzer@merlin.biologie.uni-jena.de
Journal of Enzyme Inhibition
|August 13, 1999
Summary
Researchers developed novel thrombin inhibitors by modifying a known compound. The most effective analog, Ph-CH2-SO2-D-Cha-Pro-4-(amidomethyl) amidinopiperidine 11, demonstrated potent and selective inhibition with a Ki of 0.27 nM.
Area of Science:
- Medicinal Chemistry
- Biochemistry
- Pharmacology
Background:
- Thrombin is a key enzyme in the coagulation cascade, making it a target for anticoagulant therapies.
- Developing potent and selective thrombin inhibitors is crucial for managing thrombotic disorders.
Purpose of the Study:
- To synthesize and evaluate novel C-terminal analogs of the thrombin inhibitor D-Phe-Pro-agmatine.
- To identify compounds with improved potency and selectivity against thrombin.
Main Methods:
- Synthesis of various analogs, including those with modifications to the guanidino group and derived from diamines.
- Biochemical assays to determine inhibition constants (Ki) and evaluate clotting activity.
Main Results:
- Analogs with alkylated guanidino groups exhibited poor activity.
- Ph-CH2-SO2-D-Cha-Pro-4-(amidomethyl) amidinopiperidine 11 emerged as the most potent and selective inhibitor (Ki = 0.27 nM).
- Phenol derivatives, while potent (Ki = 130 nM), showed reduced activity in clotting assays.
Conclusions:
- Structural modifications at the C-terminus can significantly impact thrombin inhibitory activity.
- The cyclic and basic residue in the P1-position of analog 11 is critical for its high potency and selectivity.
- Replacing the amidino group with a hydroxyl group reduces in vivo efficacy despite maintaining in vitro potency.