4-((R)-2-{[6-((S)-3-Methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carbonyl]amino}-3-phosphonopropionyl)piperazine-1-carboxylic Acid Butyl Ester (ACT-246475) and Its Prodrug (ACT-281959), a Novel P2Y₁₂ Receptor Antagonist with a Wider Therapeutic Window in the Rat Than Clopidogrel

Abstract

Recent post hoc analyses of several clinical trials with P2Y12 antagonists showed the need for new molecules being fully efficacious as antiplatelet agents and having a reduced propensity to cause major bleeding. We have previously reported the discovery of the 2-phenylpyrimidine-4-carboxamide analogs as P2Y12 antagonists with nanomolar potency in the disease-relevant platelet aggregation assay in human plasma. Herein we present the optimization steps that led to the discovery of clinical candidate ACT-246475 (30d). The key step was the replacement of the carboxylic acid functionality by a phosphonic acid group which delivered the most potent molecules of the program. In addition, low in vivo clearance in rat and dog was achieved for the first time. Since the bioavailability of 30d was low in rat and dog, we developed the bis((isopropoxycarbonyl)oxy)methyl ester prodrug (ACT-281959, 45). Compound 30d showed efficacy in the rat ferric chloride thrombosis model when administered intravenously as parent or orally as its prodrug 45. Moreover, 30d displays a wider therapeutic window as compared to clopidogrel in the rat surgical blood loss model.

Clinical Pharmacology of the Reversible and Potent P2Y12 Receptor Antagonist ACT‐246475 After Single Subcutaneous Administration in Healthy Male Subjects

“…2 Following thrombosis, ADP, which is released at the site of vascular damage and atherosclerotic plaque disruption, 3 can bind G protein-coupled purinergic P2Y 1 and P2Y 12 receptors that are found mainly on the surface of platelets. 4 The P2Y 1 receptor triggers rapid and transient aggregation, whereas signaling from the P2Y 12 receptor causes sustained and irreversible aggregation leading to thrombus growth in pathological conditions. 5 Two main classes of P2Y 12 receptor antagonists are currently approved for the treatment of acute coronary syndromes.…”

“…4 The P2Y 1 receptor triggers rapid and transient aggregation, whereas signaling from the P2Y 12 receptor causes sustained and irreversible aggregation leading to thrombus growth in pathological conditions. 5 Two main classes of P2Y 12 receptor antagonists are currently approved for the treatment of acute coronary syndromes. Thienopyridines (ie, clopidogrel and prasugrel) are inactive oral prodrugs requiring metabolic conversion to irreversibly bind and inactivate the P2Y 12 receptor.…”

“…5 Two main classes of P2Y 12 receptor antagonists are currently approved for the treatment of acute coronary syndromes. Thienopyridines (ie, clopidogrel and prasugrel) are inactive oral prodrugs requiring metabolic conversion to irreversibly bind and inactivate the P2Y 12 receptor. 6 In contrast, ticagrelor (for oral use) and cangrelor (for intravenous use) are nonthienopyridine receptor antagonists that reversibly bind the P2Y 12 receptor with a quicker onset of action compared to thienopyridine compounds.…”

“…Thienopyridines (ie, clopidogrel and prasugrel) are inactive oral prodrugs requiring metabolic conversion to irreversibly bind and inactivate the P2Y 12 receptor. 6 In contrast, ticagrelor (for oral use) and cangrelor (for intravenous use) are nonthienopyridine receptor antagonists that reversibly bind the P2Y 12 receptor with a quicker onset of action compared to thienopyridine compounds. 7,8 In the landscape of P2Y 12 receptor antagonists, the need for an early intervention has been highlighted by the guidelines of the European Society of Cardiology 9 and the American College of Cardiology/American Heart Association, 10 which identified the prehospital phase as the most critical in reducing mortality and reiterated that efforts must be made to reduce the delay for treatment initiation.…”

“…ACT-246475 is a potent, reversible, and selective nonthienopyridine antagonist of the P2Y 12 receptor that is being developed for subcutaneous (SC) selfadministration using an injector for the early treatment intervention of a suspected acute myocardial infarction. 11 Preclinical studies using the ferric chloride model in rats showed that ACT-246475 displays a wider therapeutic window with respect to bleeding risk than clopidogrel 12 and ticagrelor.…”