ticagrelor and pyrimidine

In this Letter we describe SAR investigation on the cyclopentyl-triazolol-pyrimidine scaffold in pursuit of new oral P2Y12 inhibitors. Different synthetic routes were developed for variations at the cyclopentyl core. Optimization finally led to compound 2d which was advanced into preclinical development based on better potency and safety profile in comparison to ticagrelor.

Topics: Administration, Oral; Animals; Cyclopentanes; Dogs; Dose-Response Relationship, Drug; Humans; Molecular Structure; Platelet Aggregation; Platelet-Rich Plasma; Purinergic P2Y Receptor Antagonists; Pyrimidines; Rats; Receptors, Purinergic P2Y12; Structure-Activity Relationship; Triazoles

P2Y(12) plays an important role in regulating platelet aggregation and function. This receptor is the primary target of thienopyridine antiplatelet agents, the active metabolites of which bind irreversibly to the receptor, and of newer agents that can directly and reversibly modulate receptor activity.. To characterize the receptor biology of the first reversibly binding oral P2Y(12) antagonist, ticagrelor (AZD6140), a member of the new cyclopentyltriazolopyrimidine (CPTP) class currently in phase III development.. Ticagrelor displayed apparent non-competitive or insurmountable antagonism of ADP-induced aggregation in human washed platelets. This was investigated using competition binding against [(3)H]ADP, [(33)P]2MeS-ADP and the investigational CPTP compound [(125)I]AZ11931285 at recombinant human P2Y(12). Functional receptor inhibition studies were performed using a GTPgammaS-binding assay, and further binding studies were performed using membranes prepared from washed human platelets.. Radioligand-binding studies demonstrated that ticagrelor binds potently and reversibly to human P2Y(12) with K(on) and K(off) of (1.1 +/- 0.2) x 10(-4) nm(-1) s(-1) and (8.7 +/- 1.4) x 10(-4) s(-1), respectively. Ticagrelor does not displace [(3)H]ADP from the receptor (K(i) > 10 mum) but binds competitively with [(33)P]2MeS-ADP (K(i) = 4.3 +/- 1.3 nm) and [(125)I]AZ11931285 (K(i) = 0.33 +/- 0.04 nm), and shows apparent non-competitive inhibition of ADP-induced signaling but competitive inhibition of 2MeS-ADP-induced signaling. Binding studies on membranes prepared from human washed platelets demonstrated similar non-competitive binding for ADP and ticagrelor.. These data indicate that P2Y(12) is targeted by ticagrelor via a mechanism that is non-competitive with ADP, suggesting the existence of an independent receptor-binding site for CPTPs.

Topics: Adenosine; Adenosine Diphosphate; Animals; Binding Sites; Blood Platelets; Cell Membrane; CHO Cells; Cricetinae; Cricetulus; Humans; Kinetics; Platelet Aggregation; Protein Binding; Pyrimidines; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Signal Transduction; Ticagrelor