title: Design and synthesis of highly constrained factor Xa inhibitors: amidine-substituted bis(benzoyl)--diazepan-2-ones and bis(benzylidene)-bis(gem-dimethyl)cycloketones.
abstract: 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.
authors.affiliation: Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, 900 S. Ashland Avenue, M/C 870, Chicago, IL 60607-7173, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Cui
authors.forename: David
authors.initials: D
authors.lastname: Crich
authors.forename: Donald
authors.initials: D
authors.lastname: Wink
authors.forename: Matthew
authors.initials: M
authors.lastname: Lam
authors.forename: Arnold L
authors.initials: AL
authors.lastname: Rheingold
authors.forename: David A
authors.initials: DA
authors.lastname: Case
authors.forename: WenTao
authors.initials: W
authors.lastname: Fu
authors.forename: Yasheen
authors.initials: Y
authors.lastname: Zhou
authors.forename: Mohan
authors.initials: M
authors.lastname: Rao
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Olson
authors.forename: Michael E
authors.initials: ME
authors.lastname: Johnson
mesh_terms: 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
chemical_list: C483138:2,7-bis((Z)-p-amidinobenzylidene)-3,3,6,6-tetramethylcycloheptanone; D003508:Cycloheptanes; D000990:Antithrombin III; D012697:Serine Endopeptidases