The composition and sequence specificity of Pro-Ala-Lys-OH for the thrombolytic activities of P6A and related oligopeptides

A class of novel N-(3S-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-l-amino acid derivatives: their synthesis, anti-thrombotic activity evaluation, and 3D QSAR analysis

“…Though the anti-thrombotic therapy of anticoagulants, anti-platelet drugs and thrombolytic drugs are well established, to improve the prevention and treatment of ischemic symptoms, more potent and safer compounds are urgently needed, and a lot of efforts have been devoted to the design of anti-thrombotic drug. However, many candidates of anti-thrombotic drug fail to exert their therapeutic potential mainly due to their poor bioavailability, which led us to pay more attention to the development of GPIIb/IIIa antagonist of small molecules with desirable pharmacodynamic and pharmacokinetic properties [7][8][9][10][11][12][13]. Recently, intestinal peptide transport system is successfully utilized to increase bioavailability [14][15][16] and we reported our new design as drug candidates in the form of dipeptide analogues that can be readily absorbed across the intestinal brush border membrane via the peptide transport system.…”

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.…”

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

“…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).…”