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

Tsugumi Fujita, Takeru Nose, Masahide Nakajima, Yoshihisa Inoue, Tommaso Costa, Yasuyuki Shimohigashi

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

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. 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, β-Mercaptopropionyl (βMp) 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. β-Mercaptopropionyl derivatives were also inactive as antagonists. However, Npys-containing analogs were found to inhibit the agonist activity of SFLLRNP. In particular, SNpys-βMp-(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.

Original languageEnglish
Pages (from-to)174-179
Number of pages6
JournalJournal of biochemistry
Volume126
Issue number1
DOIs
Publication statusPublished - 1999

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology

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