Chemical Properties
Tirofiban is an Off-White to Pale Yellow Solid. It is soluble in organic solvents such as ethanol, DMSO, and dimethyl formamide, which should be purged with an inert gas. The solubility of tirofiban in these solvents is approximately 30 mg/ml.
Originator
Aggrastat,Merck and Co., Inc.
Uses
Tirofiban is a nonpeptide GP IIb?/IIIa antagonist that binds reversibly to IIb?/IIIa receptors. Tirofiban is a non-peptide reversible antagonist of the platelet integrin glycoprotein (GP) IIbIIIa receptor used as an antiplatelet drug.
Definition
ChEBI: A member of the class of piperidines that is L-tyrosine in which a hydrogen attached to the amino group is replaced by a butylsulfonyl group and in which the hydrogen attached to the phenolic hydroxy group is replaced by a 4-(piperidin-4-y
)butyl group.
Manufacturing Process
The synthesis of tirofiban starts by reaction of tyrosine with bis-trimethylsilyl
trifluoraceramide to give a derivative in which both functions -OH and COOH_x0002_are protected. Treatment of this intermediate with butylsulfonyl chloride gives
the corresponding sulfonamide derivative; the quite labile silyl groups are then
removed under mildly acidic conditions to give N-butylsulfonyl-tyrosine. In a
parallel scheme, 4-picoline is converted to its anion by means of butyl lithium;
this gives 4-(4-chlorobutyl)-pyridine on alkylation with 1-bromo-3-
chloropropane. The reaction of this compound with N-butylsulfonyl-tyrosine in
presence of NaOH gives the ether 2-butylsulfonyaminol-3-[4-pyridin-4-ylbutoxy-phenyl]propionic acid. Hydrogenation over palladium on charcoal then
reduce the pyridine ring to a piperidine to afford the fibrinogen receptor
antagonist tirofiban.
Therapeutic Function
Fibrinogen receptor antagonist
General Description
Tirofiban is a nonpeptide that appears unrelatedchemically to eptifibatide, but actually has many similarities.The chemical architecture incorporates a systemthat is mimicking the RGD moiety that is present in eptifibatide.This can be seen in the distance between the nitrogenof the piperidine ring, which mimics the basic nitrogen ofarginine in the RGD sequence, and the carboxylic acid,which mimics the acid of aspartate in the RGD sequence.The basic nitrogen and the carboxylic acid of tirofiban areseparated by approximately 15 to 17? (16–18 atoms). Thisis the optimum distance seen in the RGD sequence of theplatelet receptor. Tirofiban is useful in treating non–Q wavemyocardial infarction and unstable angina.
Clinical Use
Tirofiban is a member of a new class of antithrombotic agents known as the “ fibans”.
These compounds have a structural similarity to disintegrin, which was originally isolated from
snake venoms. The location of the –COO-
and NH3+
in the fibans is identical to the distance
between the same functional groups of the RGD loop of disintegrin, and as a result, the fibans are
able to effectively block the binding of fibrinogen to the GPIIb/IIIa receptor in an reversible manor.
Drug interactions
Potentially hazardous interactions with other drugs
Iloprost: increased risk of bleeding.
Heparin: increased risk of bleeding
Metabolism
Tirofiban is eliminated largely unchanged in the urine, with some biliary excretion in the faeces.
Mode of action
Tirofiban is a reversible antagonist that inhibits platelet aggregation by reversibly binding to the receptor glycoprotein (GP) IIb/IIIa of human platelets, thus preventing the binding of fibrinogen. Inhibition of platelet aggregation occurs in a dose- and concentrationdependent manner.?
References
[1] Tetrahedron, 1993, vol. 49, # 26, p. 5767 - 5776
[2] Patent: CN104447509, 2016, B. Location in patent: Paragraph 0040-0042
