N²-Aroylanthranilamide Inhibitors of Human Factor Xa

Abstract

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).

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

“…198 K ass represents the apparent association constant and is approximately equal to 1/K i . 199 During follow-on SAR studies, it was discovered that the 4-hydroxy substitution was not essential to the antifactor Xa activity and that a wide range of substituents were also tolerated at the 4-position, as shown in 180-182.…”

Current trends in quantitative structure activity relationships on FXa inhibitors: Evaluation and comparative analysis

“…A QSAR study was presented by Kunal Roy et al on human factor Xa inhibitors N 2 -aroylanthranilamides, which were synthesized by Yee et al 62 It has been suggested for these derivatives that the phenyl ring at R 1 interacts with small, hydrophobic and less solvent-exposed S1 region of FXa, where as the R 2 substituent interacts with relatively more solvent-exposed S4 region.…”

“…Masters and his group reported 83 inhibitors of FXa in which they used selected hydrophobic groups for occupying both the S1 and S4 binding domains of the enzyme. They described the SAR of altering the linkage of the 1-(4-pyridyl)piperidine to the central ring to optimize the placement of this group in the S4 site of FXa and toward this end, they prepared various urethane and urea derivatives (Table IX) 62 expanding their SAR studies, showed that only small planar substituents could be accommodated in the A-ring for binding to the S1 site of the human FXa.…”

“…They described the SAR of altering the linkage of the 1-(4-pyridyl)piperidine to the central ring to optimize the placement of this group in the S4 site of FXa and toward this end, they prepared various urethane and urea derivatives (Table IX) 62 expanding their SAR studies, showed that only small planar substituents could be accommodated in the A-ring for binding to the S1 site of the human FXa. Thus, they reversed of the Aring amide link in 1,2 dibenzamidobenzenes to a new series of N 2 -Aroylanthranilamides Table X.…”

A Novel Fragment Recommendation Workflow using Direct and Indirect Transfer of SAR According to Integrated Similarities of Scaffold Motifs and SAR Trends: Application to Identifying Factor Xa Inhibitors

“…DX-9065a, which is the progenitor of small-molecule fXa inhibitors, was found to possess an amidine moiety that binds the S1 pocket [1], and numerous structurally similar amidine derivatives were investigated as well [2]. Other studies of fXa inhibitors revealed that anthranilamide derivatives with a 4-methoxyphenyl group occupy the S1 binding pocket of fXa [3][4][5]. These studies led numerous researchers to study the replacement of amidine moieties in the fXa inhibitor motifs with non-amidines such as 4-methoxyphenyl, 4-chlorophenyl, or 5-chloropyridyl groups [2].…”