HEME 06: Chemistry of Anticoagulants Flashcards
Indirect Thrombin (Factor IIa) Inhibitors
Heparin
- highly negatively charged – sulfate groups
- strong electrostatic interactions with positively charged ions – ie. Ca2+
- strong electrostatic interactions with surfaces – ie. factor Xa and thrombin (1:1 ratio)
Indirect Thrombin (Factor IIa) Inhibitors
Pentasaccharide Sequence
- 2-0-3-1-2 sulfation pattern
- binds to positively charged patch on antithrombin(III) to activate inhibition of clotting factors
Indirect Thrombin (Factor IIa) Inhibitors
What does thrombin (inactive) inhibition involve?
direct interaction with extended mucopolysaccharide chain of heparin across antithrombin(III) and exosite 2 on thrombin
Indirect Factor Xa Inhibitors
What does Factor Xa inhibition involve?
heparin does not bind to exosite on factor Xa (inactive) as a requirement for AT(III) to function
Indirect Thrombin (Factor IIa) Inhibitors
Unfractioned Heparin vs. LMWH
- LMWH specificity – shorter chain to inhibit thrombin, modifications at reducing and non-reducing ends
What are some indirect thrombin (factor IIa) inhibitors?
- enoxaparin
- tinzaparin
- dalteparin
- nadroparin
Indirect Factor Xa Inhibitors
Fondaparinux
- highly sulfated pentasaccharide that activates AT(III)
- acts as indirect inhibitor of factor Xa only (NOT thrombin) due to its minimal length – most selective LMWH
- methoxy substituent at C-1 to form acetal (locked structure) – native heparin sugar ends are hemiacetals
What are the advantages of LMWH over UFH?
- enhanced specificity binding
- more predictable
- longer half-life – longer heparins are susceptible to cleavage
- better bioavailability
Direct Factor Xa Inhibitors
Rivaroxaban
- oxazolidinone group provides elbow to ‘L’ shape for binding
- chlorothiophene moiety interrogates deep S1 subsite
Direct Factor Xa Inhibitors
Apixaban
- bicyclic group provides elbow to ‘L’ shape for binding
- p-methoxyphenyl moiety interrogates deep S1 subsite
Direct Factor Xa Inhibitors
Edoxaban
Direct Thrombin Inhibitors
Hirudin
- hirudin N-terminus occludes thrombin active site – first three residues form parallel ꞵ-sheet w/ enzyme
- anionic C-terminus of hirudin blocks exosite 1 (fibrin binding site)
- not orally bioavailable
Direct Thrombin Inhibitors
Bivalirudin
- binds to thrombin active site and exosite 1
- similar to hirudin – bivalirudin binds to and inhibits thrombin in bivalent fashion
- D-Phe residue in N-terminus binds better than L-Phe
- peptide is inactivated by proteolytic cleavage (t1/2 = 25 min under normal renal function)
Direct Thrombin Inhibitors
Argatroban
- argatroban binds only to thrombin active site
- D-Phe-Pro-Arg (S3-S2-S1) functionality is reflected in argatroban binding to thrombin – similar groups occupy same subsites
- argatroban is racemic mixture of 21(R) and 21(S) diastereomers – 21(S) is 2x more potent
Direct Thrombin Inhibitors
Dabigatran
- orally bioavailable
- non-peptidomimetic prodrug that is positively charged in acidic conditions (ie. stomach acid)
- coated with tartaric acid pellets within drug capsule to maintain low pH for absorption in stomach and intestine
- removal of ester groups yields zwitterion across broad pH range
Coumarins
Describe the role vitamin K plays in coagulation.
fat-soluble compound required for post-translational modification (formation of γ-carboxyglutamate/Gla) of proteins involved in coagulation cascade (factors II, VII, IX, X, and proteins C and S)
Coumarins
Vitamin K1 (Phylloquinone)
- comes from plant sources – ie. green leafy vegetables
- can be converted to vitamin K2 for use in blood coagulation
Coumarins
Vitamin K2 (Menaquinone-N)
- contains isoprenoid tail of variable length
Coumarins
Vitamin K Cycle
- zymogen (inactive) to zymogen (active) via vitamin K-dependent gamma-glutamyl carboxylate
- active zymogen has dicarboxylate (2 COOH’s) that coordinate Ca2+ for interaction with phospholipids on platelets)
- vitamin K epoxide (oxidized form) to vitamin K quinone via vitamin K epoxide reductase (VKOR)
- vitamin K quinone to vitamin K hydroquinone (reduced form) via vitamin K 2,3-quinone reductase
- vitamin K hydroquinone (reduced form) to vitamin K epoxide (oxidized form) via loss of electrons
Coumarins
What do coumarins act on?
inhibit VKOR
Coumarins
Illustrate the conversion of coumarin to the anticoagulant dicoumarol.
coumarin oxidation by fungi leads to vitamin K antagonist dicoumarol (anticoagulant)
Coumarins
Warfarin
- exists mainly as mixture of cyclic hemiketal diastereomers with open-chain tautomer as a minor component in solution
- suggested that warfarin’s hemiketal matches vitamin K hemiketal formed in vivo
