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Phenyltriazolinones as potent factor Xa inhibitors
Mimi L Quan1, Donald J P Pinto, Karen A Rossi
1Research and Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, USA. mimi.quan@bms.com
Bioorganic & Medicinal Chemistry Letters
|January 27, 2010
Summary
Phenyltriazolinone acts as a potent P1 inhibitor for coagulation factor Xa. Structural analysis reveals a reoriented Asp189 side chain, creating a larger S1 pocket for this novel substrate.
Area of Science:
- Biochemistry
- Structural Biology
- Medicinal Chemistry
Background:
- Coagulation factor Xa (FXa) is a critical enzyme in the blood coagulation cascade.
- FXa is a validated target for anticoagulant therapies.
- Development of novel FXa inhibitors is ongoing.
Purpose of the Study:
- To identify and characterize novel P1 moieties for FXa inhibitors.
- To elucidate the structural basis for the interaction of phenyltriazolinone with FXa.
Main Methods:
- Co-crystallization of FXa with phenyltriazolinone-based inhibitors.
- X-ray crystallography to determine inhibitor-FXa complex structures.
- Structure-based analysis of binding interactions.
Main Results:
- Phenyltriazolinone was identified as a novel and potent P1 moiety for FXa.
- X-ray structures revealed that Asp189 side chain reorients upon inhibitor binding.
- A novel, larger S1 binding pocket is formed, accommodating the phenyltriazolinone P1 group.
Conclusions:
- Phenyltriazolinone represents a promising scaffold for developing FXa inhibitors.
- The observed structural adaptation in the S1 pocket offers new insights for inhibitor design.
- This discovery could lead to improved anticoagulant drug development.
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