Synthesis, Characterization, and Structure−Activity Relationships of Amidine-Substituted (Bis)benzylidene-Cycloketone Olefin Isomers as Potent and Selective Factor Xa Inhibitors

Abstract

Factor Xa (FXa) is a trypsin-like serine protease that plays a key role in blood coagulation linking the intrinsic and extrinsic pathways to the final common pathway of the coagulation cascade. During our initial studies, we observed facile photochemical conversion of the known FXa/tPA inhibitor, BABCH ¿(E,E)-2, 7-bis(4-amidinobenzylidene)cycloheptan-1-one, 1a, to the corresponding (Z,Z) olefin isomer, 1c (FXa K(i) = 0.66 nM), which was over 25,000 times more potent than the corresponding (E,E) isomer (1a, FXa K(i) = 17 000 nM). In order to determine the scope of this observation, we expanded on our initial investigation through the preparation of the olefin isomers in a homologous series of cycloalkanone rings, 4-substituted cyclohexanone analogues, and modified amidine derivatives. In most cases the order of potency of the olefin isomers was (Z,Z) > (E,Z) > (E,E) with the cycloheptanone analogue (1c) showing the most potent factor Xa inhibitory activity. In addition, we found that selectivity versus thrombin (FIIa) can be dramatically improved by the addition of a carboxylic acid group to the cycloalkanone ring as seen with 8c (FXa K(i) = 6.9 nM, FIIa K(i) > 50,000 nM). Compounds with one or both of the amidine groups substituted with N-alkyl substituents or replaced with amide groups led to a significant loss of activity. In this report we have demonstrated the importance of the two amidine groups, the cycloheptanone ring, and the (Z,Z) olefin configuration for maximum inhibition of FXa within the BABCH template. The results from this study provided the foundation for the discovery of potent, selective, and orally active FXa inhibitors.

2,5-Bis(4-chlorobenzylidene)cyclopentanone

“…Bis(arylmethylidene) cycloalkanones have been reported to exhibit promising non-linear optical properties (Yu et al, 2000). In addition, these compounds are widely used as precursors for the synthesis of biologically active heterocycles (Guilford et al, 1999). In view of the importance of bis-chalcones, we report herein on the synthesis and crystal structure of title compound.…”

New spiro (thio) barbiturates based on cyclohexanone and bicyclo [3.1.1]heptan-6-one by nonconcerted [1+5] cycloaddition reaction and their conformational structures

“…The crossed-aldol condensation reaction is an efficient route for the synthesis of α,α'-bis(substituted benzylidene)cycloalkanones as precursors for the synthesis of biological pyrimidine derivatives [1][2][3][4] These compounds have gained a lot of attention due to their uses as agrochemical, pharmaceutical and perfume intermediates [5][6][7][8] and as liquid crystal polymer units [9]. Among these reactions, the aldol condensation reaction is useful for the formation of carbon-carbon bonds in many kinds of carbonyl compounds [10][11][12].…”

“…[5.5]undecane -1,5,9-trione (7ca'd'') [46] (50), 69 (100, base peak), 41 (27). [5.5] [5.5] 3 or C 5' ), 114.1 (C-ar. ), 128.6 (C-ar.…”

Novel Synthesis and Crystal Structures of Two α, α′-bis-Substituted Benzylidene Cyclohexanones: 2,6-Bis-2-nitro(benzylidene)cyclohexanone and 2,6-Bis-4-methyl(benzylidene)cyclohexanone

“…Bis(substituted-benzylidene) cycloalkanones are very important synthetic precursors for synthesis of biologically active pyrimidine derivatives [1,2]. These compounds have gained lots of attention due to their uses as agrochemical, pharmaceutical, and perfume intermediates and as liquid crystal polymer units [3][4][5].…”