Design and synthesis of highly constrained factor Xa inhibitors: amidine-Substituted bis(benzoyl)-[1,3]-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.
Pharmacology, Toxicology and Pharmaceutical Science
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Agricultural and Biological Sciences
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Other
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Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 3. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 15 September 2015.
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