Active site-directed thrombin inhibitors--II. Studies related to arginine/guanidine bioisosteres.
A series of N-arylsulfonylarginine amides was synthesized wherein the guanidine or arginine moiety was isosterically replaced by a number of heterocyclic functionalities. These compounds were evaluated as potential active-site inhibitors of thrombin. Bisamidines 11a-n showed a similar SAR to that of simple arginine compounds. The ex vivo clotting time measurement of 11d after ip dosing showed prolongation of clotting time in rats.
St Laurent
D R
DR
Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT 06492-7660, USA.
Balasubramanian
N
N
Han
W T
WT
Trehan
A
A
Federici
M E
ME
Meanwell
N A
NA
Wright
J J
JJ
Seiler
S M
SM
D000818:Animals; D000991:Antithrombins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001120:Arginine; D001665:Binding Sites; D001777:Blood Coagulation / Q000187:drug effects; D015195:Drug Design; D006146:Guanidines; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*
D000991:Antithrombins; D006146:Guanidines; D007202:Indicators and Reagents; D015842:Serine Proteinase Inhibitors; D001120:Arginine; D013917:Thrombin