title: 7-fluoroindazoles as potent and selective inhibitors of factor Xa.
abstract: 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.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, Welsh and McKean Roads, Spring House, Pennsylvania 19477-0776, USA.
authors.forename: Yu-Kai
authors.initials: YK
authors.lastname: Lee
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Parks
authors.forename: Tianbao
authors.initials: T
authors.lastname: Lu
authors.forename: Tho V
authors.initials: TV
authors.lastname: Thieu
authors.forename: Thomas
authors.initials: T
authors.lastname: Markotan
authors.forename: Wenxi
authors.initials: W
authors.lastname: Pan
authors.forename: David F
authors.initials: DF
authors.lastname: McComsey
authors.forename: Karen L
authors.initials: KL
authors.lastname: Milkiewicz
authors.forename: Carl S
authors.initials: CS
authors.lastname: Crysler
authors.forename: Nisha
authors.initials: N
authors.lastname: Ninan
authors.forename: Marta C
authors.initials: MC
authors.lastname: Abad
authors.forename: Edward C
authors.initials: EC
authors.lastname: Giardino
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Damiano
authors.forename: Mark R
authors.initials: MR
authors.lastname: Player
mesh_terms: 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
chemical_list: D065427:Factor Xa Inhibitors; D007191:Indazoles; D015842:Serine Proteinase Inhibitors; D015951:Factor Xa