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.
In the preparation of anti-thrombotic agents the 2- and 3-positions of 3S-tetra-hydroisoquinoline-3-carboxylic acid (THIQA) were simultaneously modified with amino acids to form 20 novel N-(3S-N-aminoacyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)amino acids (8a-t). On an in vitro platelet aggregation model 8a-t selectively inhibit ADP-induced platelet aggregation and their IC(50) values are leas than 3.5 nM. On an extracorporeal circulation of arterioveinos cannula model of rats both orally and intraveously effective doses of 8a-t are less than 30 nmol/kg. Cerius(2) based stereoview of explores 8a-t having highly unfolded conformation. 3D QSAR analysis gives the importance of the unfolded conformation to high in vitro anti-platelet aggregation and in vivo anti-thrombotic potency rational understanding.
Zhang
Xiaoyi
X
College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China.
Wang
Wei
W
Cheng
Shenling
S
Zhao
Ming
M
Zheng
Meiqing
M
Chang
Heng Wei
HW
Wu
Jianhui
J
Peng
Shiqi
S
D000818:Animals; D000991:Antithrombins / Q000737:chemistry* / Q000494:pharmacology; D002264:Carboxylic Acids / Q000737:chemistry* / Q000494:pharmacology; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017208:Rats, Wistar; D013055:Spectrophotometry, Infrared
D000991:Antithrombins; D002264:Carboxylic Acids; D010975:Platelet Aggregation Inhibitors