Background— Ticagrelor is the first reversibly binding oral P2Y 12 receptor antagonist. This is the first study to compare the onset and offset of platelet inhibition (IPA) with ticagrelor using the PLATO (PLATelet inhibition and patient Outcomes) trial loading dose (180 mg) with a high loading dose (600 mg) of clopidogrel. Methods and Results— In a multicenter, randomized, double-blind study, 123 patients with stable coronary artery disease who were taking aspirin therapy (75 to 100 mg/d) received ticagrelor (180-mg load, 90-mg BID maintenance dose [n=57]), clopidogrel (600-mg load, 75-mg/d maintenance dose [n=54]), or placebo (n=12) for 6 weeks. Greater IPA (20 μmol/L ADP, final extent) occurred with ticagrelor than with clopidogrel at 0.5, 1, 2, 4, 8, and 24 hours after loading and at 6 weeks ( P 50% IPA (98% versus 31%, P 70% IPA (90% versus 16%, P P P =NS). IPA for ticagrelor on day 3 after the last dose was comparable to clopidogrel at day 5; IPA on day 5 for ticagrelor was similar to clopidogrel on day 7 and did not differ from placebo ( P =NS). Conclusions— Ticagrelor achieved more rapid and greater platelet inhibition than high-loading-dose clopidogrel; this was sustained during the maintenance phase and was faster in offset after drug discontinuation. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00528411.

Randomized Double-Blind Assessment of the ONSET and OFFSET of the Antiplatelet Effects of Ticagrelor Versus Clopidogrel in Patients With Stable Coronary Artery Disease The ONSET/OFFSET Study

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(09)62191-7.pdf

Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study

Recently, there has been an increasing use of the cyclopropyl ring in drug development to transition drug candidates from the preclinical to clinical stage. Important features of the cyclopropane ring are, the (1) coplanarity of the three carbon atoms, (2) relatively shorter (1.51 A) C–C bonds, (3) enhanced π-character of C–C bonds, and (4) C–H bonds are shorter and stronger than those in alkanes. The present review will focus on the contributions that a cyclopropyl ring makes to the properties of drugs containing it. Consequently, the cyclopropyl ring addresses multiple roadblocks that can occur during drug discovery such as (a) enhancing potency, (b) reducing off-target effects, (c) increasing metabolic stability, (d) increasing brain permeability, (e) decreasing plasma clearance, (f) contributing to an entropically more favorable binding to the receptor, (g) conformational restriction of peptides/peptidomimetics to prevent proteolytic hydrolysis, and (h) altering drug pKa to reduce its P-glycoprotein e...

The "Cyclopropyl Fragment" is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules.

AimsMore intense platelet-directed therapy for acute coronary syndrome (ACS) may increase bleeding risk. The aim of the current analysis was to determine the rate, clinical impact, and predictors o ...

/pdf/bleeding-complications-with-the-p2y12-receptor-antagonists-z6sf8wrky0.pdf

Bleeding complications with the P2Y12 receptor antagonists clopidogrel and ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial.

2012 update to the Society of Thoracic Surgeons guideline on use of antiplatelet drugs in patients having cardiac and noncardiac operations.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1538-7836.2009.03527.x

B.-M. Wissing

Papers

Ticagrelor binds to human P2Y(12) independently from ADP but antagonizes ADP-induced receptor signaling and platelet aggregation.