Design and synthesis of para-fluorophenylalanine amide derivatives as thrombin receptor antagonists.

Abstract

An antagonist specific for the thrombin receptor is expected to be a remedy for thrombosis. Structure-activity studies of thrombin receptor-tethered ligand SFLLRNP have revealed the importance of the Phe-2-phenyl group in receptor recognition and the replacement of the Phe-2 by para-fluorophenylalanine [(p-F)Phe] was found to enhance its activity [Nose, T. et al. (1993) Biochem. Biophys. Res. Commun. 193, 694-699]. In order to obtain a small sized antagonist, a series of (p-F)Phe derivatives was designed and synthesized novel structural elements essential for receptor interactions being introduced at both the N and C-termini. beta-Mercaptopropionyl (betaMp) or its derivative activated by S-3-nitro-2-pyridinesulphenyl (Npys) was introduced at the N-terminus, and phenylmethyl amines were coupled to the C-terminus. All compounds were inactive when assayed for human platelet aggregation, indicating that they are not agonists. beta-Mercaptopropionyl derivatives were also inactive as antagonists. However, Npys-containing analogs were found to inhibit the agonist activity of SFLLRNP. In particular, SNpys-betaMp-(p-F)Phe-NH-R [R = -CH(C6H5)2 and -CH2-CH-(C6H5)2] potently suppressed platelet aggregation. The results suggested that (p-F)Phe can be used as a structural core to construct an effective antagonist conformation.

• Authors: T Fujita, T Nose, M Nakajima, Y Inoue, T Costa, Y Shimohigashi
• Journal: Journal of biochemistry (J Biochem) Vol. 126 Issue 1 Pg. 174-9 (Jul 1999) ISSN: 0021-924X [Print] England
• PMID: 10393336 (Publication Type: Journal Article)

Chemical References

• 3-nitro-2-pyridinesulfenyl-beta-mercaptopropionyl-4-fluorophenylalanine 2,2-diphenylethyl amide
• Amides
• Oligopeptides
• Peptide Fragments
• Platelet Aggregation Inhibitors
• Receptors, Thrombin
• thrombin receptor peptide SFLLRNP
• p-Fluorophenylalanine

Topics

• Amides (chemistry)
• Drug Design
• Drug Evaluation, Preclinical
• Humans
• Inhibitory Concentration 50
• Oligopeptides (chemical synthesis, pharmacology)
• Peptide Fragments (pharmacology)
• Platelet Aggregation Inhibitors (chemical synthesis, pharmacology)
• Receptors, Thrombin (agonists, antagonists & inhibitors)
• Structure-Activity Relationship
• p-Fluorophenylalanine (analogs & derivatives)