885591-04-8Relevant articles and documents
7-Fluoroindazoles as potent and selective inhibitors of factor Xa
Lee, Yu-Kai,Parks, Daniel J.,Lu, Tianbao,Thieu, Tho V.,Markotan, Thomas,Pan, Wenxi,McComsey, David F.,Milkiewicz, Karen L.,Crysler, Carl S.,Ninan, Nisha,Abad, Marta C.,Giardino, Edward C.,Maryanoff, Bruce E.,Damiano, Bruce P.,Player, Mark R.
, p. 282 - 297 (2008/09/17)
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 ?) 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 β-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 (ΔΔG ≈ 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.
