Design and synthesis of para-fluorophenylalanine amide derivatives as thrombin receptor antagonists.
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.
Laboratory of Structure-Function Biochemistry, Department of Molecular Chemistry, Graduate School of Science, Kyushu University, Fukuoka, 812-8581, Japan.
T
T
Fujita
T
T
Nose
M
M
Nakajima
Y
Y
Inoue
T
T
Costa
Y
Y
Shimohigashi
D000577:Amides / Q000737:chemistry; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D018179:Receptors, Thrombin / Q000819:agonists / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D010135:p-Fluorophenylalanine / Q000031:analogs & derivatives*
C121946:3-nitro-2-pyridinesulfenyl-beta-mercaptopropionyl-4-fluorophenylalanine 2,2-diphenylethyl amide; D000577:Amides; D009842:Oligopeptides; D010446:Peptide Fragments; D010975:Platelet Aggregation Inhibitors; D018179:Receptors, Thrombin; C086309:thrombin receptor peptide SFLLRNP; D010135:p-Fluorophenylalanine