TICAGRELOR

Ticagrelor, a new platelet aggregation inhibitor successfully developed by AstraZeneca (U.S.), is the world’s first reversible combination orally-administered P2Y12 adenosine diphosphate receptor antagonist.
It is used to reduce cardiovascular death and heart attacks in patients with acute coronary syndrome (ACS.) Rapid onset after oral administration, and can effectively improve symptoms of patients with ACS. Thienopyridines is a reversible P2Y12 inhibitor, so it is particularly applicable towards patients who need to undergo anticoagulant therapy before surgery.

Reversibly acts on the 2 purine receptor (purinoceptor 2, P2,) subtype P2Y12, of vascular smooth muscle cells (VSMC,) does not require metabolic activation, and has a significant inhibitory effect on platelet aggregation induced by adenosine diphosphate (ADP.)

Ticagrelor was approved by the U.S. Food and Drug Administration (FDA) on the basis of PLATO clinical studies. PLATO was a 43 country, 862 center randomized, double-blind, multi-centered study which included 18,624 patients hospitalized for ACS. Patients were randomly given either aspirin plus ticagrelor, or aspirin plus clopidogrel, two antiplatelet regimens. The study showed a 16% reduction in risk of heart attack, stroke, or death in the group taking Ticagrelor compared to those who took clopidogrel. The PLATO study demonstrated the benefits of Ticagrelor for patient survival, and is currently widely recommended as a treatment strategy for ACS. In addition, at the same time it reduces operative myocardial infarction and thrombosis after stent implantation, it also does not increase the overall risk of fatal bleeding and other serious adverse effects.
Ticagrelor however has two shortcomings. First, it must be taken twice a day, compared to once a day for clopidogrel, and secondly, it may cause adverse effects such as breathing difficulties, significantly more than with the latter. Its half-life is only 12 hours, and taken twice a day, a challenge for patients with poor compliance. In practice, it has also been found that around 20% of patients treated with clopidogrel do not follow their prescriptions, and these patients are even less likely to take the prescribed doses when using ticagrelor. Thus, as a rapidly reversible drug, direct withdrawal will likely increase the risk of acute thrombosis, causing myocardial infection or stroke.

Ticagrelor is a reversible antagonist of the platelet purinergic P2Y₁₂ receptor (K_i = 14 nM; IC₅₀ = 1.8 μM), which is the main receptor responsible for ADP-induced platelet aggregation. It functions by directly changing the conformation of the P2Y₁₂ receptor to inhibit ADP binding. Formulations containing ticagrelor have been used to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome.

In December 2010, the P2Y₁₂ receptor antagonist ticagrelor (also known as AZD6140) was approved in Europe for the treatment of acute coronary syndrome (ACS), a condition that covers several clinical symptoms with the potential to cause acute myocardial ischemia (MI). ADP binds to two purinergic receptors, the P2Y1 and P2Y₁₂ receptors. The action of ADP binding to the P2Y₁₂ receptor results in activation of the GP Ⅱb/Ⅲa (integrin) receptor.GP Ⅱb/Ⅲa initiates and prolongs platelet aggregation, which in turn results in the cross-linking of platelets through fibrin and finally thrombus formation. Inhibition of ADP stimulation of the P2Y₁₂ receptor has been found to be an effective strategy for managing the atherothrombotic events associated with ACS and potentially resulting from percutaneous coronary intervention (PCI, stent implantation) .

White Solid

Astra-Zeneca (United Kingdom)

Ticagrelor, the first reversible oral P2Y12 receptor antagonist, provides faster, greater, and more consistent ADP-receptor inhibition than Clopidogrel. Used in the treatment of acute coronary syndromes (ACS).

Ticagrelor is the first reversibly binding oral P2Y12 receptor antagonist, also inhibits CYP2C9 and 4-hydroxylation with IC50 of 10.5 μM and 8.2 μM respectively

ChEBI: A triazolopyrimidine that is an adenosine isostere; the cyclopentane ring is similar to ribose and the nitrogen-rich [1,2,3]triazolo[4,5-d]pyrimidine moiety resembles the nucleobase adenine. A platelet aggregation inhibitor which is used for p evention of thromboembolic events in patients with acute coronary syndrome.

Brilique and Possia in the European Union

Ticagrelor, discovered and developed by AstraZeneca, is a platelet adenosine diphosphate (ADP) P2Y12 (P2T) reversible receptor antagonist approved in the E.U. in 2010 and launched in Germany and the UK in 2011 for the treatment of patients with acute coronary syndromes (ACS). It was approved in the U.S. and Canada in 2011 following successful clinical trial results in patients with ACS which showed it to be superior to preexisting drugs for reducing death due to vascular causes. Ticagrelor is an oral drug indicated for use in combination with acetylsalicylic acid (aspirin) for the prevention of atherothrombotic events in adult patients with ACS (unstable angina, non-ST elevation myocardial infarction (NSTEMI), or ST elevation myocardial infarction (STEMI)). Unlike its competitors prasugrel and clopidogrel, which require bioactivation, ticagrelor is not a prodrug and does not require in vivo activation. It has a rapid onset of action, relatively rapid reversibility, greater potency, and exhibits consistency in platelet inhibition. Following dosing, ticagrelor reaches Cmax in about 1.5 h, with formation of a major metabolite with equipotent intrinsic activity to the parent compound.

The initial discovery of the drug and SAR studies were published in 2007, including the initial discovery patent applications. Since then, a number of patents have been published with various improvements made for largescale synthesis of the drug. While the molecule has been synthesized using various modifications of the common intermediates, the large-scale preparation proceeds via a convergent strategy involving the coupling of three key intermediates as shown in the Scheme below.


Several routes to the synthesis of cyclopentyl amino alcohol 235 have been reported. Most of these routes are based on reaction of cyclopentene acetate 238 with the appropriate amine, which is commercially available. Interestingly, one route targeting deuterated ticagrelor used a nitroxide Diels¨CAlder reaction with cyclopentadiene to incorporate the amine into the ring system. The most likely process-scale preparation of the key cyclopentyl amine required for ticagrelor is highlighted in the scheme below.

Commercially available enantiopure acetate 238 was reacted with sodium di-tert-butyloxy diimide under catalytic palladiummediated amination conditions to give bis-Boc amide 239 in 92% yield. Dihydroxylation of cyclopentene 239 using catalytic osmium tetraoxide and N-methyl morpholine N-oxide (NMO) in THF/water quantatively resulted in the cis-diol 240. The free amine was liberated with 6 N HCl followed by in situ ketalizaion of the cis-diol hydrochloride salt 241 in 92% yield. Cbz carbamate 242 was quantitatively synthesized from 241 under standard conditions. Alcohol 242 was treated with potassium t-butoxide and bromoethyl acetate (243), the ester intermediate of which was reduced in situ with lithium borohydride to alcohol 244 in 86% overall yield (two steps). Hydrogenolysis at 1.2 bar of hydrogen pressure with 5% Pd/C gave amino alcohol intermediate 235 in 83% yield. This amine (235) was mixed with oxalic acid to provide the oxalate salt in 82% yield, which was subsequently used for the final synthesis of ticagrelor.
The large-scale preparation of ticagrelor necessitated the synthesis of dichloroamino pyrimidine thioether 236, for which there are several reported routes. The synthesis is initiated with the construction of thiol barbituric acid 247 (Scheme below). This intermediate was formed from the reaction of dimethyl malonate (245) with thiourea (246) in the presence of sodium methoxide. These conditions provided the sodium salt of the pyrimidone thiol 247 in 83% yield, which was isolated via filtration from the reaction mixture. Salt 247 was then reacted with propyliodide in aqueous methanolic sodium hydroxide followed by HCl quench to provide the desired thioether 248 in 76% yield. Nitration of pyrimidinol thioether 248 was achieved by treatment with fuming nitric acid in acetic acid, furnishing the nitro pyrimidinol 249 in 75% yield. Subsequent bis-chlorination with POCl3 converted 249 to dichloropyrimidine thioether 250 in near quantitative yield. In an earlier publication, a selective reduction of the nitro dichloropyrimide thioether 250 was demonstrated by hydrogenation at 3 bar hydrogen pressure using 3%Pt/0.6%V/C catalyst to provide the amino dichloropyrimidine thioether 236 in 95% yield. It is also of note that for the larger kilo-scale reaction, selective hydrogenation was accomplished with Pt/V/C (2% Pt; 1% V on carbon) catalyst with 8 bar of hydrogen pressure to give the crude amino dichloropyrimidine thioether 236.

While a number of routes have been described for the preparation of cyclopropyl amine intermediate 237,184¨C187,193¨C196 the large scale route used is described (Scheme below).195 Condensation of malonic acid and 3,4-difluorobenzaldehyde (251) with piperidine in pyridine gave acid 252 in 88% yield after acidic work-up. Acid chloride 253 was prepared using thionyl chloride, which was followed by esterification with L-menthol and pyridine to give Lmenthol ester 254 in 93% over 2 steps. Cyclopropanation with dimethylsulfoxonium methylide in DMSO gave desired trans cyclopropane 255 in 40% yield and 92% ee after recrystallization. Hydrolysis of the ester followed by reaction with thionyl chloride gave acid chloride 257 in 61% overall yield in two steps. Acid chloride 257 was then reacted with sodium azide in the presence of sodium carbonate and tetrabutyl ammonium bromide in a biphasic mixture of toluene and water to give the acyl azide intermediate, which was immediately subjected to warm toluene to furnish, after acidic workup, the key intermediate cyclopropyl amine 237 in 88% yield and 92% ee. This enantioenriched intermediate was then mixed with R-(-)-mandelic acid to provide the mandelic acid salt of amine 237 (258).

With all three intermediates available from the above mentioned routes, the final assembly of ticagrelor was accomplished as outlined in the scheme below. First, oxalate salt of cyclopentyl amine 235 was coupled with dichloroaminopyrimidine thioether 236 in the presence of triethylamine and at elevated temperature to give diamine intermediate 259 in 88% yield after crystallization. Diamine 259 was then subjected to diazotization with sodium nitrite in acetic acid and toluene at ??30??C, leading to the formation of triazole 260. This intermediate was immediately reacted with 258 (madelic acid salt of cyclopropyl amine 237) to give intermediate 261, which was subsequently taken forward to the final deprotection step. Reaction of ketal 261 with concentrated HCl in methanol and toluene at 15??C provided ticagrelor (XXII) in 82¨C90% yield over the 3 steps.

Potentially hazardous interactions with other drugs
Antibacterials: concentration possibly increased by clarithromycin - avoid; concentration possibly increased by erythromycin; concentration reduced by rifampicin.
Anticoagulants: concentration of dabigatran increased.
Antifungals: concentration increased by ketoconazole - avoid.
Antivirals: concentration possibly increased by atazanavir and ritonavir - avoid.
Cardiac glycosides: concentration of digoxin increased.
Ciclosporin: possibly increases ciclosporin concentration.
Ergot alkaloids: concentration of ergot alkaloids possibly increased.
Lipid-regulating drugs: concentration of simvastatin increased - increased risk of toxicity.

CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of the active metabolite and their interactions with other CYP3A substrates ranges from activation through to inhibition. The systemic exposure to the active metabolite is approximately 30-40
% of that obtained for ticagrelor. The primary route of ticagrelor elimination is via hepatic metabolism. The primary route of elimination for the active metabolite is most likely via biliary secretion.

[1] zhou d1, andersson tb, grimm sw. in vitro evaluation of potential drug-drug interactions with ticagrelor: cytochrome p450 reaction phenotyping, inhibition, induction, and differential kinetics. drug metab dispos. 2011 apr;39(4):703-10.
[2] li y1, landqvist c, grimm sw. disposition and metabolism of ticagrelor, a novel p2y12 receptor antagonist, in mice, rats, and marmosets. drug metab dispos. 2011 sep;39(9):1555-67. doi: 10.1124/dmd.111.039669. epub 2011 jun 13.