Design, synthesis, and inhibition of platelet aggregation for some 1-o-chlorophenyl-1,2,3,4-tetrahydroisoquinoline derivatives.
Based on ticlopidine active as an ADP receptor antagonist for inhibiting platelet aggregation in clinical test, and upon finding (+/-)-1,2-substituted-7-sulfonylamide/amide-1,2,3,4-tetrahydroisoquinoline (11-31) inhibited of platelet aggregation, a series of (+/-)-1-o-chlorophenyl-2-substituted-tetrahydroisoquinoline derivatives was designed and synthesized. Four analogs proved to be potential antiplatelet aggregation agents, and compound 9 (TQP-3, applying for patent) which inhibits ADP-induced human platelet aggregation with IC50 values of approximately 0.206 nM was the most active. Compound 2 is more active than compound 1, which (Type I) is similar to ticlopidine. This is because there is a spacial hindrance in compound 1, and the o-chloro group of compound 2 may play the same a role as o-chloro group of ticlopidine. On the other hand, with the different substitutions at different positions on the 2-substituted phenylacyl group, their inhibition of platelet aggregation differs. These compounds with m-substituted group (5, 7, 9) showed a higher IC50 value for inhibiting ADP-induced human platelet aggregation than those with o-substituted group (4, 6) or p-substituted group (3, 8). It was observed that their inhibition is bromine-substituted derivative (9), chlorine-substituted derivative (7), and nitro-substituted derivative (5) in turn. Moreover, these compounds (Type II) may be more similar to clopidogrel than to ticlopidine due to the acyl group at 2 position of the nucleus playing a role as the ester group of clopidogrel. It was conjectured that these analogs function as a potential antiplatelet aggregation role by acting as ADP receptor antagonists.
Yang
Jie
J
State Key Laboratory of Pharmaceutical Biotechnology, Department of Biochemistry, College of Life, 22 Hankou Road, Nanjing University, Nanjing 210093, PR China. luckyjyj@sina.com.cn
Hua
Wei-Yi
WY
Wang
Fu-Xiang
FX
Wang
Zhi-Yuan
ZY
Wang
Xiang
X
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000077144:Clopidogrel; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D058919:Purinergic P2 Receptor Antagonists; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D013988:Ticlopidine / Q000031:analogs & derivatives*
D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D044005:Tetrahydroisoquinolines; C096775:1,2,3,4-tetrahydro-1-phenylisoquinoline; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D013988:Ticlopidine