Diarylsulfonamides as selective, non-peptidic thrombin inhibitors.
Based on the structures of aminopyridine thrombin inhibitors (1), a series of aminoalkyl- and guanidinoalkyl-substituted diarylsulfonamides were prepared. The most potent derivative, N-[3-(4-guanidinobutoxy)-5-methyl-phenyl]-benzenesulfonamide (6c) had Ki = 0.18 microM for thrombin and did not inhibit trypsin, plasmin, or factor Xa. Comparison of the X-ray structures of the thrombin/1b and the thrombin/6c complexes revealed important aspects which govern the binding of such diarylsulfonamides to thrombin.
Weber
I R
IR
Pharmazeutisch-Chemisches Institut der Universität, Heidelberg, Germany.
Neidlein
R
R
von der Saal
W
W
Grams
F
F
Leinert
H
H
Strein
K
K
Engh
R A
RA
Kucznierz
R
R
D000991:Antithrombins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014961:X-Ray Diffraction
D000991:Antithrombins; D013449:Sulfonamides