Key result
Compounds 5 and 6 were discovered as highly potent factor Xa inhibitors with Ki values of 0.065 nM and 0.045 nM, respectively, demonstrating enhanced binding in the factor Xa S1 site.
Why the study?
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The discovery of 2-(6-chloro-3-methylsulfonyl)-naphthyl as an optimal factor Xa S1 binding element yielded highly potent and selective in vitro factor Xa inhibitors, providing a scaffold for further anticoagulant drug development.
Provides a scaffold for factor Xa inhibitor development; leaves open in vivo efficacy and clinical translation.
Based upon the biphenyl 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides reported in our previous communications, we designed and discovered 2-(6-chloro-3-methylsulfonyl)-naphthyl as an optimal factor Xa S1 binding element. Employing a key Diels-Alder reaction of 1,4-dihydro-2,3-benzoxathiin-3-oxide with maleic anhydride and a key Cu(I)-mediated methylsulfonylation, we prepared two biphenyl 1-(2-(6-chloro-3-methylsulfonyl)-naphthyl)-1H-pyrazole-5-carboxylamides as highly potent factor Xa inhibitors with K(i) values of 0.065 nM and 0.045 nM respectively, and demonstrated the synergistically enhanced binding interaction in the factor Xa S1 site.
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Jia et al. (2009) studied this question. 1-(2-(6-Chloro-3-methylsulfonyl)-naphthyl)-1H-pyrazole-5-carboxylamides (Compounds 5 and 6) was evaluated on Factor Xa inhibition (IC50 and Ki). Compounds 5 and 6 were discovered as highly potent factor Xa inhibitors with Ki values of 0.065 nM and 0.045 nM, respectively, demonstrating enhanced binding in the factor Xa S1 site.
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