Design and synthesis of highly constrained factor Xa inhibitors: amidine-substituted bis(benzoyl)--diazepan-2-ones and bis(benzylidene)-bis(gem-dimethyl)cycloketones.
Two conformationally constrained templates have been designed to provide selective inhibitors of the coagulation cascade serine protease, Factor Xa (FXa). The most active inhibitor, 2,7-bis[(Z)-p-amidinobenzylidene)]-3,3,6,6-tetramethylcycloheptanone, exhibits a K(i) of 42 nM against FXa, with strong selectivity against thrombin (1000-fold), trypsin (300-fold) and plasmin (900-fold). With only two freely rotatable bonds, molecular modeling suggests that one amidine group is positioned into the S1 pocket, forming hydrogen bonds with the side chain of Asp189, similar to other amidine-based inhibitors, with the second benzamidine positioned into the S4 pocket in a position to form strong cation-pi bonding with the S4 aryl cage. We suggest that this interaction plays an important role in the specificity of these inhibitors against other serine proteases.
Cui
Jian
J
Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, 900 S. Ashland Avenue, M/C 870, Chicago, IL 60607-7173, USA.
Crich
David
D
Wink
Donald
D
Lam
Matthew
M
Rheingold
Arnold L
AL
Case
David A
DA
Fu
WenTao
W
Zhou
Yasheen
Y
Rao
Mohan
M
Olson
Arthur J
AJ
Johnson
Michael E
ME
D000990:Antithrombin III / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003508:Cycloheptanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D012697:Serine Endopeptidases / Q000378:metabolism
C483138:2,7-bis((Z)-p-amidinobenzylidene)-3,3,6,6-tetramethylcycloheptanone; D003508:Cycloheptanes; D000990:Antithrombin III; D012697:Serine Endopeptidases