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9-hydroxyazafluorenes and their use in thrombin inhibitors
Kenneth J Stauffer1, Peter D Williams, Harold G Selnick
1Department of Medicinal Chemistry, Biological Chemistry, Pharmacology, Drug Metabolism, and Molecular Systems, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. ken_stauffer@merck.com
Journal of Medicinal Chemistry
|April 2, 2005
Summary
Researchers optimized a thrombin inhibitor, developing a new compound (19b) with high potency and improved pharmacokinetic properties. This novel azafluorenyl derivative demonstrated complete efficacy in preclinical thrombosis models.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Biochemistry
Background:
- Thrombin inhibitors are crucial for anticoagulation therapy.
- Previous lead compound 1 showed promising thrombin inhibition but required optimization.
- Lipophilic groups can lead to high plasma protein binding, affecting drug efficacy.
Purpose of the Study:
- To optimize a novel thrombin inhibitor for improved potency and pharmacokinetic properties.
- To identify a lead compound with enhanced efficacy in vivo.
- To explore structure-activity relationships of azafluorenyl derivatives as thrombin inhibitors.
Main Methods:
- Systematic modification of a lead thrombin inhibitor (1).
- Synthesis and evaluation of azafluorenyl P3 isomers and N-oxide analogues.
- In vitro assays for human thrombin inhibition (K(i)) and plasma anticoagulation (APTT).
- In vivo thrombosis model in rats to assess efficacy.
- X-ray crystallography to determine stereochemistry.
Main Results:
- Compound 2, a modified lead, showed improved potency and pharmacokinetics.
- Replacing the fluorenyl group with an azafluorenyl moiety reduced plasma protein binding and enhanced in vivo efficacy.
- Optimal compound 19b exhibited high potency (K(i) = 0.40 nM), excellent pharmacokinetics (F = 55%, T(1/2) = 14 h), and complete efficacy in rats.
- X-ray crystallography confirmed the stereochemistry of 19b's azafluorenyl group.
Conclusions:
- Azafluorenyl P3 modification is an effective strategy for optimizing thrombin inhibitors.
- Compound 19b represents a highly potent and efficacious preclinical candidate for anticoagulation.
- Structural elucidation via X-ray crystallography aids in understanding drug-target interactions.