Synthesis of new class dipeptide analogues with improved permeability and antithrombotic activity

Abstract

3-( S)-1,2,3,4-Tetrahydro-β-carboline-3-carboxylic acid isolated from A. Chinese G. Don was found to possess moderate anti-aggregation activity, but with poor bioavailability. To improve its pharmacological property, we designed and synthesized a series of novel dipeptide analogues by incorporating tetrahydro-β-carboline-3-carboxylic acid skeleton as an amino acid surrogate (∗Trp). It turned out these dipeptide analogues exhibited good membrane permeability based on in vitro Caco-2 cell monolayers permeability assay. As a result, the overall biological properties of these molecules were significantly improved depending on the nature of the amino acid residues introduced onto the 3-position of the tetrahydro-β-carboline moiety. It was very interesting to notice that these dipeptide analogues ( 5b, c, h, i, n, o, p, q) displayed a remarkable dual antiaggregatory activity in both of ADP- and PAF-induced platelet aggregation assay, and their aggregation response was significantly higher than that of aspirin ( p < 0.01). In addition, these dipeptide analogues were observed for the dose-dependent antithrombotic effect using in vivo rat arterial thrombosis model. The potency of antithrombotic activity of 5h, i, n, p was significantly higher than that of aspirin ( n = 12, p < 0.01) at equal dose (5 μmol/kg).