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.

• Authors: Eva Caroff, Francis Hubler, Emmanuel Meyer, Dorte Renneberg, Carmela Gnerre, Alexander Treiber, Markus Rey, Patrick Hess, Beat Steiner, Kurt Hilpert, Markus A Riederer
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 23 Pg. 9133-53 (Dec 10 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 26550844 (Publication Type: Journal Article)

Chemical References

• Carboxylic Acids
• Piperazines
• Platelet Aggregation Inhibitors
• Prodrugs
• Purinergic P2Y Receptor Antagonists
• Pyrrolidines
• Clopidogrel
• Ticlopidine

Topics

• Animals
• Carboxylic Acids (chemistry, pharmacokinetics, therapeutic use)
• Clopidogrel
• Dogs
• Drug Discovery
• Esterification
• Humans
• Male
• Piperazines (chemistry, pharmacokinetics, therapeutic use)
• Platelet Aggregation (drug effects)
• Platelet Aggregation Inhibitors (chemistry, pharmacokinetics, therapeutic use)
• Prodrugs (chemistry, pharmacokinetics, therapeutic use)
• Purinergic P2Y Receptor Antagonists (chemistry, pharmacokinetics, therapeutic use)
• Pyrrolidines (chemistry, pharmacokinetics, therapeutic use)
• Rats
• Rats, Wistar
• Thrombosis (drug therapy)
• Ticlopidine (analogs & derivatives, therapeutic use)