January 26, 2023

This is an educational video on Clopidogrel for the Chemistry for Drug Discovery Module of the Second Year of the BSc Pharmacology and Drug Discovery Course.

Clopidogrel sold under the name plavix is a second-generation antiplatelet drug belonging to the finite pyridine family clopidogrel works who’s used the risk of stroke and other cardiovascular diseases by inhibiting platelet clot formation clopidogrel is an all formulation often taken alongside aspirin for maximal efficiency the typical clock with herbal formulation

Contains 75 micrograms of the drug itself the drug has a long onset time of around 2 hours how the desired effects can last for 3 to 5 days clapping dog rule was designed in 1977 and patented in 1982 in a joint venture by stenography and bristol-myers squibb co the drug was fda approved and released onto the market in 1998 where it was very successful before its

Patent expiry in 2012 it was the second best selling drug globally and in 2010 grossed over 9 billion u.s. dollars clapping dog works by inhibiting the pt y12 receptor which upon binding to his adp agonist induces platelet aggregation a fundamental step in atherosclerosis atherosclerosis is where plaque develops in the blood vessels this can be very dangerous

Because it causes an increase in blood pressure subsequently increasing the risk of stroke aneurysms and his coma corpses atherosclerosis develops when low-density lipoproteins known as ldls are deposited in the blood vessels ldls will eventually become oxidized and this initiator chronic inflammatory response including leukocytes macrophages and lymphocytes it

Also activates platelets agent a critical step in the forming of the plaque the platelets aggregate via the binding of adp to the p2 wide 12 receptor which in turn activates gpi ia and gpi i be receptors that cause cross links with the village in the adhesion of the platelets acts to direct the inflammatory cells to the plaque the platelets also carry a significant

Amount of stromal derive factor one known as sdf one sdf is a potent chemical for the so i was recruited in the inflammatory response recruited macrophages try to remove the ldl but could not effectively remove it resulting in the formation of foam cells increasing the mass of the ldl forming a plaque this plaque is known as atherosclerosis drugs such as to copper

Diene and clopidogrel covalently bind to the p 2 y 12 receptor and stop the platelets from aggregating final pyridine drugs are family of irreversible p2 white swirled receptor inhibitors whose structure contains a five-pin ring fused with tetra hydro pyridine ring the first thyroid paradine drug introduced was to clobber dean discovered by sanofi in 1972 while

Screening for novel anti-inflammatory molecules its mechanism of action was unknown until after the development of the second generation of drug so copper dean was released globally in 1991 but upon its release research started with the development of a novel analog as patients experienced many hematological adverse effects some patients experienced neutropenia a

Deficiency in neutrophil cells the most prevalent leukocyte in the bloodstream meaning the body’s ability to fight infection is greatly reduced there were also some reported cases of thrombotic thrombocytopenic purpura also known as ttp a disorder leading to the formation of small blood clots forming in the smaller blood vessels all over the body these clots result

In reduced platelet and red blood cell count and ultimately leads to failure of major organs such as the brain heart and kidneys along with these serious adverse effects typical side effects of the clotting treatment include diarrhea nausea dyspepsia and abdominal pain a novel analog was developed in the form of copra doggerel which began preclinical trials in

1987 and was released onto the market 11 years later the major notes will change the analog was the replacement of a hydrogen with an ester group through changing this group the incidence of ttp dropped to 4 per million patients treated the synthesis of clopidogrel can be completed by many different reactions the one that is shown is generally considered to be the

Most effective method as determined by sanofi the company who produced clopidogrel the first step in this mechanism was the formation of methyl ester continued refluxing with chlorinated mandelic acid with methanol in the presence of hydrochloric acid produced methyl men delayed the product form was chlorinated using thionyl chloride which leads to the formation

Of alpha chloro acetate the latter was then displaced with phi e no pyridine through an sn2 reaction which finally leads to the formation of the drugs final structure the problem found in these methods was that there produced racemic mixtures this was problematic because only the dexstar rotary clapping doggerel variant was the active compound and the lever rotary

Proper doral was the inactive compound and had no binding interactions with the p2 y12 receptor this problem was overcome by treating the racemic mixture with leave a rotary cam for 10 sulphonic acid in acetone 2 for salt 19 this was recrystallized from acetone to produced in an ant america pure dexstar rotary copper doggerel this is the current way of synthesis

For clopidogrel on a large scale setting clapper doggerel is actually a prodrug and is only active after has undergone two sequential oxidations by cytochrome p450 enzymes known as sip enzymes to form its active metabolite firstly clopidogrel is transported into the liver via the action of the abc b1 transporter this is where the two sequential oxidation steps

Occur the first oxidation converts clopper doggerel into two oxide copper doggerel via the action of sip 1a to sip to c19 and sit to b6 the first step involves the addition of a ketone through an epoxy i’d formation the major enzyme responsible is sitting 1a to the second oxidative step converts to oxide copper doggerel into the active metabolite via the action

Of sip 3a for sip to c9 sip 3 a5 sip to b6 and sip to c19 as well as the to workstation steps there is also an enzyme called ces one that can deactivate clopidogrel to oxide copper doggerel and the active metabolite ces 1 is the major hydrolytic enzyme in the liver and performs approximately 95% of the total hydrolytic activity in the liver ces one hydrolyzes

Clopidogrel to oxide copper doggerel and the active metabolite when adp activates platelets it binds to the p2 y12 receptor and the p2 y one receptor both receptors must be activated with platelet aggregation to occur once activated the gi protein that is bound to the p2 y twelve receptor is liberated into the g alpha and g beta gamma subunits the g alpha subunit

Inhibits the dental cyclase reducing the production of cyclic adenosine monophosphate this in turn inhibits protein kinase a and activates vasodilator stimulated phosphate protein known as a vas vas causes platelet degranulation and from vox in production activating gpib and gpi ia causing the release of religion this ultimately causes platelet aggregation

Clopidogrel binds to the p2 y 12 receptor covalently forming a disulfide bond with the thyle group of the active metabolite and the cysteine residue in the binding pocket the adp cannot activate both necessary scepters to cause aggregation this means the platelets cannot aggregate for the rest of their life cycle stopping the formation of atherosclerosis clopidogrel

Was introduced as a safer alternative to tackle codeine reducing the serious adverse effects and to improve antiplatelet action but it’s not free of its own adverse effects along with some incidents of ttp patients may experience hemorrhage which is blood loss in the circulatory system this can occur either internally or externally through openings such as the

Mouth and nose incidence of hemorrhage is aggravated upon joule administration with aspirin although co-administration increases the drugs antiplatelet ability this can explain the adverse effects application of both drugs has an additive effect further inhibiting the ability of platelets to induce clots both those necessary and atherosclerosis this leads to

Increased bleeding this excessive bleeding leads to other common side effects such as easily bruising caused by internal bleeding to the interstitial tissues associated with blunt trauma other common side effects include nausea itching and heart them there is potential for cooperative rules interact with other drugs used in treatment for alternative conditions

In cellular models clopper doctor was found to inhibit sip to c19 and so may increase plasma concentrations of drugs that metabolizes for example potassium channel blocker table you tonight which can lead to adverse systemic side effects in 2009 the fda restricted clopper dogle administration with proton pump inhibitors omeprazole and asymmetrical due to its

Detrimental interactions clopidogrel is metabolized to its active form by sip to c19 however variety and genotyping leads to inactivity of the drug due to variation in the enzyme it is suggested that as much as 14% of patients our cytochrome p450 poor metabolizers receiving minimal benefit from clopidogrel treatment and our it’s an almost four times greater risk

For cardiovascular related disease in order to combat this inherited clopidogrel resistance the third-generation thyroid pyridine drug prasugrel was brought to market in 2009 by companies daiichi sankhya and eli lilly along with its thigh no protein predecessors prasugrel is a prodrug but becomes metabolized in a different means due to two significant changes that

The general thyroid pyridine structure observed in clopidogrel firstly the ester group found in clopidogrel was switched to a ketone group attached to a tri cyclists carbon structure making it more metabolically stable secondly the hydrogen at the two position in the thigh pain ring was replaced with an ester group this ester group addition shifted the metabolic

Process to be conducted by esterase enzymes conquering the issue of sip to c19 variation at this point the sucrose metabolism converges with clopidogrel and to klopper diem as the non active fire lactone undergoes ring-opening thanks to the sip enzymes

Transcribed from video
Clopidogrel By Ellie Hyde