Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity.

Abstract

The discovery of an exceptionally potent series of thrombin receptor (PAR-1) antagonists based on the natural product himbacine is described. Optimization of this series has led to the discovery of 4 (SCH 530348), a potent, oral antiplatelet agent that is currently undergoing Phase-III clinical trials for acute coronary syndrome (unstable angina/non-ST segment elevation myocardial infarction) and secondary prevention of cardiovascular events in high-risk patients.

• Authors: Samuel Chackalamannil, Yuguang Wang, William J Greenlee, Zhiyong Hu, Yan Xia, Ho-Sam Ahn, George Boykow, Yunsheng Hsieh, Jairam Palamanda, Jacqueline Agans-Fantuzzi, Stan Kurowski, Michael Graziano, Madhu Chintala
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 51 Issue 11 Pg. 3061-4 (Jun 12 2008) ISSN: 0022-2623 [Print] United States
• PMID: 18447380 (Publication Type: Journal Article)

Chemical References

• Alkaloids
• Furans
• Lactones
• Naphthalenes
• Piperidines
• Platelet Aggregation Inhibitors
• Pyridines
• Receptors, Thrombin
• himbacine
• vorapaxar

Topics

• Administration, Oral
• Alkaloids (chemical synthesis, pharmacokinetics, pharmacology)
• Animals
• Furans (chemical synthesis, pharmacokinetics, pharmacology)
• Humans
• In Vitro Techniques
• Lactones (chemical synthesis, pharmacokinetics, pharmacology)
• Macaca fascicularis
• Naphthalenes (chemical synthesis, pharmacokinetics, pharmacology)
• Piperidines (chemical synthesis, pharmacokinetics, pharmacology)
• Platelet Aggregation Inhibitors (chemical synthesis, pharmacokinetics, pharmacology)
• Pyridines (chemical synthesis, pharmacokinetics, pharmacology)
• Rats
• Receptors, Thrombin (antagonists & inhibitors)
• Structure-Activity Relationship