7-fluoroindazoles demonstrated about 60-fold greater factor Xa inhibitory potency compared to corresponding indazoles without the 7-fluoro group.
A novel 7-fluoroindazolyl moiety significantly increases the potency of factor Xa inhibitors by forming a key hydrogen bond with the enzyme's beta-sheet domain.
Effect estimate: 60-fold greater
We have developed a novel series of potent and selective factor Xa inhibitors that employ a key 7-fluoroindazolyl moiety. The 7-fluoro group on the indazole scaffold replaces the carbonyl group of an amide that is found in previously reported factor Xa inhibitors. The structure of a factor Xa cocrystal containing 7-fluoroindazole 51a showed the 7-fluoro atom hydrogen-bonding with the N-H of Gly216 (2.9 A) in the peptide backbone. Thus, the 7-fluoroindazolyl moiety not only occupied the same space as the carbonyl group of an amide found in prior factor Xa inhibitors but also maintained a hydrogen bond interaction with the protein's beta-sheet domain. The structure-activity relationship for this series was consistent with this finding, as the factor Xa inhibitory potencies were about 60-fold greater (DeltaDelta G approximately 2.4 kcal/mol) for the 7-fluoroindazoles 25a and 25c versus the corresponding indazoles 25b and 25d. Highly convergent synthesis of these factor Xa inhibitors is also described.
Lee et al. (Thu,) conducted a other in Factor Xa inhibition. 7-fluoroindazoles vs. corresponding indazoles was evaluated on Factor Xa inhibitory potency (60-fold greater). 7-fluoroindazoles demonstrated about 60-fold greater factor Xa inhibitory potency compared to corresponding indazoles without the 7-fluoro group.