Identification, synthesis and bioassay for the metabolites of P6A

Peptides by Extension at the N‐ or C‐terminii of Lysine

“…Peptide coupling reactions were successfully carried out between N ‐(Z‐ or Fmoc‐ α ‐aminoacyl)benzotriazoles 1a–g derived from Phe, Ala, Trp, Met, and Z ε ‐Lys 2a in partially aqueous solution in the presence of Et 3 N over 30–45 min (Scheme 1). By comparison, literature methods (3,4,8,10,11,13,17–19,26) require 18–24 h for completion. 1 H‐NMR analysis for each compound revealed two sets of doublets for the two –NH protons ranging from 7.4 to 8.3 ppm.…”

“…α ‐Lysine (Fig. 1) occur in various biologically active peptides, for example, in the active portions of adrenocorticotropic hormones (1), melanotropic hormones (2), thrombolytically active therapeutic agents such as P6A (obtained from fibrinogen degradation; 3–5), adhesive proteins of marine mussel (6,7), chemotactic peptides (8), biocompatible telomers (9), hybrid peptides (10), and analogs‐like somatostatin (11). Consequently, considerable efforts have had been made to incorporate Lys residues in the peptide chain extension.…”

“…Previous preparations of peptides containing Z ε ‐lysine utilized coupling reagents‐like carbodiimides (3–7,10,12–18) and BOP (9). Peptide coupling has also been achieved using the mixed anhydride method (8,11,19–22), the azide method (23–25), the active ester method (formyl‐substituted nitrophenylthio esters; 26).…”

“…However, all these methodologies require long reaction times (18–24 h). For example, the coupling of N‐protected amino acid with Z ε ‐lysine or its corresponding ester in the presence of DCC/HOBT requires 18–24 h to achieve completion (3,4,8,10,11,13,17–19,26). In some cases, the final product is an ester and thus requires hydrolysis or hydrogenolysis as an additional step to obtain the desired free peptide (3,4,10,11,19,21,23–25).…”

2,3-Diamino acid modifying 3S-tetrahydroisoquinoline-3-carboxylic acids: Leading to a class of novel agents with highly unfolded conformation, selective in vitro anti-platelet aggregation and potent in vivo anti-thrombotic activity

“…However, due to undesirable bioavailability the antithrombotic candidates usually fail to exert therapeutic potential, which leads to the development of GPIIb/IIIa antagonists having good pharmacodynamic and pharmacokinetic property. [7][8][9][10][11][12][13][14] On the other hand, intestinal peptide transport system is particularly utilized to increase bioavailability. [15][16][17] Following this approach 3S-1,2,3,4-tetrahydro-isoqunoline-3-carbonylamino acid (THIQA), an anti-platelet aggregation compound, was modified to its dipeptide analogues to improve their permeability and consequently to enhance their anti-thrombotic activity.…”