7-fluoroindazoles as potent and selective inhibitors of factor Xa.
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
Yu-Kai
YK
Johnson & Johnson Pharmaceutical Research and Development, Welsh and McKean Roads, Spring House, Pennsylvania 19477-0776, USA.
Parks
Daniel J
DJ
Lu
Tianbao
T
Thieu
Tho V
TV
Markotan
Thomas
T
Pan
Wenxi
W
McComsey
David F
DF
Milkiewicz
Karen L
KL
Crysler
Carl S
CS
Ninan
Nisha
N
Abad
Marta C
MC
Giardino
Edward C
EC
Maryanoff
Bruce E
BE
Damiano
Bruce P
BP
Player
Mark R
MR
D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D015951:Factor Xa / Q000737:chemistry; D065427:Factor Xa Inhibitors; D006801:Humans; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology; D008958:Models, Molecular; D011487:Protein Conformation; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D065427:Factor Xa Inhibitors; D007191:Indazoles; D015842:Serine Proteinase Inhibitors; D015951:Factor Xa