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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