PHM 472 Antiinfectives-antitumours
Medicinal Chemistry
Antithrombotic agents
A.Vitamin K antagonists
B.Heparin and derivative substances
C.Glycoprotein IIb/IIIa inhibitors
D.Other platelet aggregation inhibitors
E.Direct thrombin inhibitors
F.Misc. antithrombotic agents
H.Thrombolytic agents
G.Anticoagulants outside the body
A. Vitamin K antagonists
Oral anticoagulants = class of pharmaceuticals that act by
antagonizing the effects of vitamin K (slow onset; if immediate
effect is required, heparin must be given concomitantly).
Generally, these anticoagulants are used to treat patients with
deep-vein thrombosis (DVT), pulmonary embolism, atrial
fibrillation, and mechanical prosthetic heart valves. Vitamin K is
required for the proper production of certain proteins involved in
the blood clotting process.Vit. K: family of compounds, with
methylnaphtoquinone nucleus + variable side chain: Vit K1, K2(20),
K2(35), K2(45), K3,
Vit K1: R =
Vit K2(35): R =
Vit K3: R =H
Biochemical Mechanism of Action of Vit K
This post-translation modification is catalyzed by an enzymes
vitamin K reductase and vitamin K epoxide reductase. Vitamin K is a
co-factor in this conversion reaction. Thus it cycles between a
reduced form and an epoxide form. Because of their structural
similarity with vitamin K coumarins are thought to bind the
enzymes, vitamin K reductase and vitamin K epoxide reductase,
without facilitating the conversion of Glu residues of prothrombin
to Gla. Thus prothrombin cannot be acted upon by factor Xa.
The most important oral anticoagulants are:
Coumarin derivatives
Indanediones
I. Coumarin derivatives
Coumarins: close similarity with naphtoquinones =
antimetabolites.
Derived from dicoumarol, isolated from decomposed sweet
clover
WarfarinacenocoumarolPhenprocoumon
And also: tioclomarolSARs: simple:
4-OH-coumarin needed for activity ( enol group).
3-Alkyl substituent: activity over H.
Other compounds used as rodenticides = brodifacoum,
bromadiolone, coumachlor, coumafuryl, etc.
Note on tautomerism: tautomers are compounds that are
interconvertible. Reaction = tautomerisation. Examples:
enolketoneimidic acidamideenamineimineII. Indanediones
1,3-Indanedione ring system developed on the basis that it is
even closer to the 1,4-naphtoquinone nucleus.
phenindioneanisindioneClorindione
Phenindione: no longer used as it may induce rare but serious
adverse effects. Replaced by anisindione, clorindione.Other =
diphenadione, fluindione.SARs:
The 2-H should be enolizable (acidic).
Side chain: lipophilic.
Some of the above compounds + others (pindone,
isovaleryl-indanedione, chlorophacinone, etc) used as
rodenticides.B. Heparin and derivative substances
1. Heparin= biological substance, mucopolysaccharide, MW:
3,000-50,000 Da. Commercial preparations: usually 12,000-15,000
Da.Usually made from pig intestines & beef lungs. It works by
activating antithrombin III, which blocks thrombin from clotting
blood.
Acidic properties (has the highest negative charge density of
any known biological molecule). also referred to as heparinic acid.
Administered as Na+ salt.Structure: made of a variably-sulphated
repeating disaccharide units.Most common monosaccharides:
GlcA= -D-glucuronic acidIdoA
= -L-iduronic acidIdoA(2S)= 2-O-sulpho--L-iduronic acid
GlcN= 2-deoxy-2-amino--D-glucopyranosyl = -D-glucosamineGlcNAc=
2-deoxy-2-acetamido--D-glucopyranosylGlcNS=
2-deoxy-2-sulphamido--D-glucopyranosylGlcNS(6S)=
2-deoxy-2-sulphamido--D-glucopyranosyl-6-O-sulphate
Most common disaccharide: IdoA(2S)-GlcNS(6S): 85% of bovine
heparin.
Other common disaccharides: GlcA-GlcNAc, GlcA-GlcNS, IdoA-GlcNS,
IdoA(2S)-GlcNS, IdoA(2S)-GlcNS(6S),2. Low molecular weight
heparins= more highly processed products. Advantage: do not require
monitoring of the activated partial thromboplastin time (aPTT or
APTT): they more predictable plasma levels) and less side
effects.
Examples: ardeparin, dalteparin, danaparoid, enoxaparin,
nadroparin, reviparin, tinzaparin, etc.
3. Fondiparinux= synthetic pentasaccharide. Apart from the
O-methyl group at the reducing end of the molecule, the identity
and sequence of the five monomeric sugar units = a sequence of five
monomeric sugar units that can be isolated after either chemical or
enzymatic cleavage of heparin and heparan sulfate (HS). This
monomeric sequence is thought to form the high affinity binding
site for the anti-coagulant factor antithrombin III (ATIII).
Binding of heparin/HS to ATIII has been shown to increase the
anti-coagulant activity of antithrombin III 1000 fold.
C. Glycoprotein IIb/IIIa inhibitors (GpIIb/IIIa inhibitors)
GpIIb/IIIa inhibitors = antiplatelet agents.Their development
arose from the understanding of Glanzmann's thrombasthenia, a
condition in which the GpIIb/IIIa is lacking.
Given intravenously (toxic orally), before angioplasty, or to
treat acute coronary syndromes. 3 drugs:
Abciximab = specific antibody
Eptifibatide = cyclic heptapeptide containing six amino acids
and one mercaptopropionyl (des-amino cysteinyl) residue. An
interchain disulfide bridge is formed between the cysteine amide
and the mercaptopropionyl moieties.
Tirofiban = non-peptide drug: the first drug whose origins can
be traced to a pharmacophore-based virtual screening lead.
D. Other platelet aggregation inhibitors
Aspirin and aloxiprin (AlOH salicylate2)
Dipyridamole (inhibits thrombus formation when given chronically
and causes vasodilation when given at high doses over short
time).
E. Direct thrombin inhibitors
Another type of anticoagulant is the direct thrombin inhibitors.
Current members of this class include small molecules and
peptides.4. Small molecules
Argatroban
Argatroban is intended for IV administration. It has a rapid
onset and rapid reversibility of its coagulant effect.
1972: Okamoto (Mitsubishi Chemical Industries) show that
thrombin promotes conversion of fibrinogen to fibrin by cutting the
Arg-Gly bond in fibrinogen. ( Research for a thrombin inhibitor
starts with:
Tosyl arginine methyl ester
Playing around with substituents ( argatroban.1990: approved in
Japan in as anticoagulant
2000: approved by FDA for prophyllaxis and treatment of
thrombosis in patient with heparin-induced thrombocytopenia.
2002: approved by FDA for usage in certain heart procedures
(ex.: percutaeous coronary interventions) with patients at risk of
heparin-induced thrombocytopenia.
2005: approved in Europe.
Ximelagatran
Ximelagatran was the first member of the drug class of direct
thrombin inhibitors that could be taken orally. It acts solely by
inhibiting the actions of thrombin.
Ximelagatran was a prodrug, being converted in vivo to the
active agent melagatran, through dealkylation and dehydroxylation
(replacing the ethyl and hydroxyl groups with hydrogen).
AstraZeneca has been investigated extensively as a replacement
for warfarin that would overcome most problems associated with it.
However, AZ announced in 2006 that it would not market ximelagatran
after reports of hepatotoxicity (liver damage) during trials.
Dabigatran
Dabigatran was developed by pharmaceutical company
Boehringer-Ingelheim.
It was discovered from a panel of chemicals with similar
structure to benzamidine-based thrombin inhibitor -NAPAP
(N-alpha-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine
piperidide), which had been known since the 1980s as a powerful
inhibitor of various serine proteases, specifically thrombin but
also trypsin. Addition of a hydrophobic side chain led to the
orally absorbed prodrug dabigatran etexilate.
-NAPAP
On March 18, 2008, the European Medicines Agency granted
marketing authorisation for dabigatran. In Canada, approval came on
June 13, 2008.5. Natural peptide: Hirudin
Hirudin = naturally occurring peptide in the salivary glands of
medicinal leeches (such as Hirudo medicinalis) that has a blood
anticoagulant property.
In 1884, the British physiologist J.B. Haycraft discovered that
the leech (Hirudo medicinalis) secreted a powerful anticoagulant,
which he named hirudin, though it was not isolated until the 1950s,
nor its structure fully determined until 1976.
Full length, hirudin is made up of 65 amino acids. These amino
acids are organised into a compact N-terminal domain containing 3
disulfide bonds and a C-terminal domain which is completely
disordered, when the protein is un-complexed in solution. Natural
hirudin contains a mixture of various isoforms of the protein.
However, recombinant techniques can be used to produce homogeneous
preparations of hirudin.6. Recombinant peptide: Lepirudin
Lepirudin = highly specific direct inhibitor of thrombin. = a
recombinant hirudin derived from yeast cells. The polypeptide
composed of 65 amino acids.
Biosynthetic molecule (lepirudin) is identical to natural
hirudin except for substitution of leucine for isoleucine at the
N-terminal end of the molecule and the absence of a sulfate group
on the tyrosine at position 63.
7. Semi-synthetic peptide: Bivalirudin
Bivalirudin = synthetic congener of the naturally occurring drug
hirudin.Bivalirudin
F. Misc. antithrombotic agentsDefibrotide is a deoxyribonucleic
acid derivative (single stranded) derived from cow lung or porcine
mucosa. It is an anticoagulant with a multiple mode of action.
Ozagrel
Inhibition of thromboxane A2-synthase (TXAS), especially in
human platelets, has been a clinical objective for many years.
1-Alkyl (N-alkyl)-imidazole derivatives have been recognized as
TXAS inhibitors since the early 1980s. Ozagrel is a 1-alkyl
imidazole derivative that acts as a selective inhibitor of TXAS
with an IC50 of 11 nM.
Ramatroban
Ramatroban = thromboxane receptor antagonist indicated for the
treatment of coronary artery disease. It has also been used for the
treatment of asthma. It was developed by the German pharmaceutical
company Bayer AG and is co-marketed in Japan by Bayer and Nippon
Shinyaku Co. Ltd. under the tradename Baynas.
G. Thrombolytic agents
All biological products:
Streptokinase: produced by -haemolytic streptococci. Least
expensive but highly antigenic.
Urokinase: physiologic thrombolytic agent produced in renal
parenchymal cells. Produced from tissue cultures and recombinant
techniques.
Alteplase: 1st recombinant tissue-type plasminogen activator,
identical to native tissue plasminogen activator.
Reteplase: 2nd generation recombinant tissue-type plasminogen
activator, synthetic, non-glycosylated, deletion mutein of native
tissue plasminogen activator
Other drugs include saruplase, ancrod, drotrecogin ,
tenecteplase, protein C, anistreplase, fibrinolysin, brinase.
H. Anticoagulants outside the body
Laboratory instruments, test tubes, blood transfusion bags, and
medical and surgical equipment will get clogged up and become
non-operational if blood is allowed to clot.
Chemicals can be added to stop blood clotting. Apart from
heparin, most of these chemicals work by binding calcium ions,
preventing the coagulation proteins from using them:
EDTA is denoted by mauve or purple caps on Vacutainer test
tubes. This chemical strongly and irreversibly binds calcium. It is
in a powdered form.
Citrate is usually in blue Vacutainer tube. It is in liquid form
in the tube and is used for coagulation tests, as well as in blood
transfusion bags. It gets rid of the calcium, but not as strongly
as EDTA. Correct proportion of this anticoagulant to blood is
crucial because of the dilution. It can be in the form of sodium
citrate or acid citrate dextrose (ACD).
Oxalate has a similar mechanism to citrate. It is the
anticoagulant used in fluoride (grey top) tubes.
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