Synthesis of new class dipeptide analogues with improved permeability and antithrombotic activity.
3-(S)-1,2,3,4-Tetrahydro-beta-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-beta-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-beta-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 micromol/kg).
Zhao
Ming
M
College of Pharmaceutical Sciences, Capital University of Medical Sciences, Beijing, 100054, PR China.
Bi
Lanrong
L
Bi
Wei
W
Wang
Chao
C
Yang
Zhe
Z
Ju
Jingfang
J
Peng
Shiqi
S
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001682:Biological Availability; D018938:Caco-2 Cells; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010539:Permeability; D010974:Platelet Aggregation / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar
D004151:Dipeptides; D005343:Fibrinolytic Agents; D001241:Aspirin