Key result
Compound 55 demonstrates potent human factor Xa inhibition with an 11.5 nM Ki.
Effect estimate: K_i = 11.5 nM
Compound 55 was identified as a highly potent human factor Xa inhibitor through structure-activity relationship optimization of N2-aroylanthranilamides.
May guide anticoagulant lead optimization; leaves open translation to clinical use.
Reversal of the A-ring amide link in 1,2-dibenzamidobenzene 1 (fXa K(ass) = 0.81 x 10(6) L/mol) led to a series of human factor Xa (hfXa) inhibitors based on N(2)-aroylanthranilamide 4. Expansion of the SAR around 4 showed that only small planar substituents could be accommodated in the A-ring for binding to the S1 site of hfXa. Bulky groups such as 4-isopropyl, 4-tert-butyl, and 4-dimethylamino were favored in the B-ring to interact with the S4 site of hfXa. The central (C) ring containing a 5-methanesulfonamido group yielded greater activity than carbamoyl groups. Combining the beneficial features from the B- and C-ring SAR, compound 55 represents the most potent hfXa inhibitor in the N(2)-aroylanthranilamide 4 series with hfXa K(ass) = 58 x 10(6) L/mol (K(i) = 11.5 nM).
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Yee et al. (2000) studied this question. N2-aroylanthranilamide inhibitors (compound 55) was evaluated on Human factor Xa inhibition (K_ass and K_i) (K_i = 11.5 nM). Compound 55 emerged as the most potent human factor Xa inhibitor in the N2-aroylanthranilamide series, demonstrating a K_i of 11.5 nM.
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