From ATP to AZD6140: The discovery of an orally active reversible P2Y12 receptor antagonist for the prevention of thrombosis

Springthorpe, Brian; Bailey, A. S.; Barton, Patrick; Birkinshaw, Timothy N.; Bonnert, Roger V.; Brown, Richard Harvey; Chapman, David; Dixon, J. Michael; Guile, Simon D.; Humphries, Robert G.; Hunt, Simon F.; Ince, Francis; Ingall, Anthony H.; Kirk, Ian P.; Leeson, Paul D.; Leff, P.; Lewis, Richard J.; Martin, Barrie; McGinnity, Dermot F.; Mortimore, Michael P.; Paine, Stuart W.; Pairaudeau, Garry; Patel, Anil S.; Rigby, Aaron; Riley, Robert J.; Teobald, Barry J.; Tomlinson, Wendy; Webborn, Peter J. H.; Willis, Paul

doi:10.1016/j.bmcl.2007.07.057

Cited by 206 publications

(145 citation statements)

References 11 publications

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“…At P2Y 12 R, 59-triphosphates were found to be partial agonists or, in some cases, antagonists (Kauffenstein et al, 2004;Springthorpe et al, 2007). In platelets, triphosphates and triphosphate mimics, such as 28-30, inhibit ADP-induced aggregation, which is consistent with P2Y 12 R antagonism.…”

Section: Medicinal Chemistry Of P2yrs: Focus On Nucleotidessupporting

confidence: 54%

Nucleotides Acting at P2Y Receptors: Connecting Structure and Function

et al. 2015

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Eight G protein-coupled P2Y receptor (P2YR) subtypes are important physiologic mediators. The human P2YRs are fully activated by ATP (P2Y 2 and P2Y 11 ), ADP (P2Y 1 , P2Y 12 , and P2Y 13 ), UTP (P2Y 2 and P2Y 4 ), UDP (P2Y 6 and P2Y 14 ), and UDP glucose (P2Y 14 ). Their structural elucidation is progressing rapidly. The X-ray structures of three ligand complexes of the G i -coupled P2Y 12 R and two of the G q -coupled P2Y 1 Rs were recently determined and will be especially useful in structure-based ligand design at two P2YR subfamilies. These high-resolution structures, which display unusual binding site features, complement mutagenesis studies for probing ligand recognition and activation. The structural requirements for nucleotide agonist recognition at P2YRs are relatively permissive with respect to the length of the phosphate moiety, but less so with respect to base recognition. Nucleotide-like antagonists and partial agonists are also known for P2Y 1 , P2Y 2 , P2Y 4 , and P2Y 12 Rs. Each P2YR subtype has the ability to be activated by structurally bifunctional agonists, such as dinucleotides, typically, dinucleoside triphosphates or tetraphosphates, and nucleoside polyphosphate sugars (e.g., UDP glucose) as well as the more conventional mononucleotide agonists. A range of dinucleoside polyphosphates, from triphosphates to higher homologs, occurs naturally. Earlier modeling predictions of the P2YRs were not very accurate, but recent findings have provided much detailed structural insight into this receptor family to aid in the rational design of new drugs.

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Section: Medicinal Chemistry Of P2yrs: Focus On Nucleotidessupporting

confidence: 54%

Nucleotides Acting at P2Y Receptors: Connecting Structure and Function

et al. 2015

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“…The chemical starting point for the development of ticagrelor was ATP, and it retains an adenosine-like core, 18 so initial specificity screens included direct binding to biotinylated ticagrelor, biotinylated adenosine, and unmodified ticagrelor in a competition assay (supplemental Figure 1). A panel of 80 antibodies that bound ticagrelor but not adenosine was taken forward for further profiling.…”

Section: Resultsmentioning

confidence: 99%

“…The affinity of MEDI2452 for ticagrelor and TAM is 20 pM, which is 100-fold greater than the 2 nM affinity of ticagrelor for its receptor P2Y 12 . 18 The crystal structure for MEDI2452 shows …”

Section: Discussionmentioning

confidence: 99%

Structural and functional characterization of a specific antidote for ticagrelor

Buchanan

Newton

Pehrsson

et al. 2015

Blood

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• In the clinic, all oral antiplatelet medicines have a risk of bleeding complications.• We present an antidote for ticagrelor that reverses its antiplatelet effect in human platelet-rich plasma and its bleeding effect in mice.Ticagrelor is a direct-acting reversibly binding P2Y 12 antagonist and is widely used as an antiplatelet therapy for the prevention of cardiovascular events in acute coronary syndrome patients. However, antiplatelet therapy can be associated with an increased risk of bleeding. Here, we present data on the identification and the in vitro and in vivo pharmacology of an antigen-binding fragment (Fab) antidote for ticagrelor. The Fab has a 20 pM affinity for ticagrelor, which is 100 times stronger than ticagrelor's affinity for its target, P2Y 12 . Despite ticagrelor's structural similarities to adenosine, the Fab is highly specific and does not bind to adenosine, adenosine triphosphate, adenosine 59-diphosphate, or structurally related drugs. The antidote concentration-dependently neutralized the free fraction of ticagrelor and reversed its antiplatelet activity both in vitro in human platelet-rich plasma and in vivo in mice. Lastly, the antidote proved effective in normalizing ticagrelor-dependent bleeding in a mouse model of acute surgery. This specific antidote for ticagrelor may prove valuable as an agent for patients who require emergency procedures. (Blood. 2015;125(22):3484-3490)

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“…In this series, it was also possible to substitute the unwieldy triphosphate group with uncharged moieties such as short alcohols or esters, thus proving that a highly anionic moiety is not needed for recognition by the P2Y 12 receptor. This discovery led to compounds such as the carbocyclic nucleoside derivative AZD6140 (28), which is an orally active P2Y 12 receptor antagonist of nanomolar affinity that inhibits platelet aggregation up to 8 h after administration (Springthorpe, 2003). The presence of the 3,4-difluorophenyl group limits the metabolism of compound 28.…”

Section: A Chemical Structure Of Agonist and Antagonist Ligandsmentioning

confidence: 99%