title: Discovery of potent, efficacious, and orally bioavailable inhibitors of blood coagulation factor Xa with neutral P1 moieties.
abstract: The bicyclic dihydropyrazolopyridinone scaffold allowed for incorporation of multiple P1 moieties with subnanomolar binding affinities for blood coagulation factor Xa. The compound 3-[6-(2'-dimethylaminomethyl-biphenyl-4-yl)-7-oxo-3-trifluoro-methyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridine-l-yl]-benzamide 6d shows good fXa potency, selectivity, in vivo efficacy and oral bioavailability. Compound 6d was selected for further pre-clinical evaluations.
authors.affiliation: Discovery Chemistry Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA. Donald.Pinto@bms.com
authors.forename: Donald J P
authors.initials: DJ
authors.lastname: Pinto
authors.forename: Robert A
authors.initials: RA
authors.lastname: Galemmo
authors.forename: Mimi L
authors.initials: ML
authors.lastname: Quan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Orwat
authors.forename: Charles
authors.initials: C
authors.lastname: Clark
authors.forename: Renhua
authors.initials: R
authors.lastname: Li
authors.forename: Brian
authors.initials: B
authors.lastname: Wells
authors.forename: Francis
authors.initials: F
authors.lastname: Woerner
authors.forename: Richard S
authors.initials: RS
authors.lastname: Alexander
authors.forename: Karen A
authors.initials: KA
authors.lastname: Rossi
authors.forename: Angela
authors.initials: A
authors.lastname: Smallwood
authors.forename: Pancras C
authors.initials: PC
authors.lastname: Wong
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.forename: Alan R
authors.initials: AR
authors.lastname: Rendina
authors.forename: Robert M
authors.initials: RM
authors.lastname: Knabb
authors.forename: Kan
authors.initials: K
authors.lastname: He
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.forename: Patrick Y S
authors.initials: PY
authors.lastname: Lam
mesh_terms: D000284:Administration, Oral; D001549:Benzamides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D016896:Treatment Outcome
chemical_list: D001549:Benzamides; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents