Antagonists of the Platelet P_2T Receptor:  A Novel Approach to Antithrombotic Therapy

Abstract

The platelet P2T receptor plays a major role in platelet aggregation, and its antagonists are predicted to have significant therapeutic potential as antithrombotic agents. We have explored analogues of adenosine triphosphate (ATP), which is a weak, nonselective but competitive P2T receptor antagonist. Modification of the polyphosphate side chain to prevent breakdown to the agonist adenosine diphosphate (ADP) and substitution of the adenine moiety to enhance affinity and selectivity for the P2T receptor led to the identification of 10e (AR-C67085MX), having an IC50 of 2.5 nM against ADP-induced aggregation of human platelets. Compound 10e was the first very potent antagonist of the P2T receptor, with a selectivity for that subtype of the P2 receptor family of >1000-fold. Further modification of the structure produced compound 10l (AR-C69931MX) having an IC50 of 0.4 nM. In vivo, at maximally effective antithrombotic doses, there is little prolongation of bleeding time (1.4-fold), which is in marked contrast to the 5-6-fold found with GPIIb/IIIa antagonists.

Design and synthesis of new bicyclic diketopiperazines as scaffolds for receptor probes of structurally diverse functionality

“…Exploration of selective agonists and antagonists modulators is most advanced at the P2Y 1 and P2Y 12 receptors, but at most of the P2Y receptors selective pharmacological probes are lacking. [22][23][24][25][26][27][28][29][30][31][32] Compound 20 was shown to antagonize signaling of the P2Y 1 receptor selectively and with moderate potency. At the P2Y 1 receptor, the previously described high affinity antagonists are nucleotide derivatives and therefore highly charged, which is highly limiting in pharmacological studies due to low bioavailability and stability.…”

“…For example, antagonists of the P2Y 1 and P2Y 12 receptors are of interest as antithrombotic agents. [22][23][24][25][26][27][28][29][30][31][32] Agonists of the P2Y 2 receptor are of interest in the treatment of pulmonary diseases, including cystic fibrosis. The P2Y 6 receptor has recently been implicated in protection against apoptosis induced by TNFα.…”

Cangrelor for the management and prevention of arterial thrombosis

“…However, GPIIb/IIIa antagonists are associated with a narrow therapeutic window since therapeutic levels of platelet inhibition are achieved at dose levels that can prolong bleeding time by some 6-7 fold, increasing the risk of major bleeding complications and hindering their extensive use [32]. This may theoretically be related to the fact that GPIIb/IIIa antagonists concurrently affect platelet aggregation and platelet activation in a linear fashion, with low levels of GPIIb/IIIa blockade being therapeutically ineffective but high levels compromising platelet function excessively (Figure 1) [33].…”

“…Various test compounds led to the identification of two therapeutically useful analogues; one of these was cangrelor, a true ATP analogue (Figure 2) that demonstrated a highly selective nature at the P 2T receptor [14]. Using human washed platelets and impedance aggregometry in vitro, cangrelor demonstrated inhibition of ADP-induced (3 µmol/L) platelet aggregation with a pIC50 of 9.35 and 79% platelet recovery in 20 minutes after cessation of infusion [32]. These properties represented a major advantage in the mechanism of action of this antithrombotic agent.…”

In search of selective P2 receptor ligands: interaction of dihydropyridine derivatives at recombinant rat P2X2 receptors

“…Carbocyclic and acyclic analogues have also been shown to have high affinity at P2Y 1 receptors, among which analogues is a ring-constrained carbocyclic bisphosphate derivative, MRS 2279 ((1R,2S,4S, 5S)-1-[(phosphato)methyl]-4-(2-chloro-6-aminopurin-9-yl)bicyclo[3.1.0]-hexane-2-phosphate), which has an IC 50 value of 52 nM (Nandanan et al, 2000). There are also high affinity antagonists at the yet uncloned P2 T receptors, such as ARL 67085 (2-propylthio-D-β,γ-dichloromethylene-ATP), which is in clinical trials as an anti-thrombotic agent (Ingall et al, 1999). Ip 5 I has been shown to be a potent antagonist of P2X 1 receptors (King et al, 1999).…”