title: Highly efficacious factor Xa inhibitors containing alpha-substituted phenylcycloalkyl P4 moieties.
abstract: We previously disclosed a series of highly potent FXa inhibitors bearing alpha-substituted (CH(2)NR(1)R(2)) phenylcyclopropyl P4 moieties in the pyrazolodihydropyridone core system. Herein, we describe our continuous SAR efforts in this series. Effects of the C-3 substitution of the pyrazolodihydropyridone core and the alpha-substitution (R group) of the cyclopropyl ring on FXa binding affinity (FXa K(i)), human plasma anticoagulant activity (PT EC(2x)) and permeability are discussed. A set of compounds obtained from optimization of the R group and the C-3 substituent were orally bioavailable in dogs. Furthermore, representative compounds were highly efficacious in the rabbit arterio-venous shunt thrombosis model (EC(50)s=29-81nM).
authors.affiliation: Research and Discovery, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543-5400, USA. jennifer.qiao@bms.com
authors.forename: Jennifer X
authors.initials: JX
authors.lastname: Qiao
authors.forename: Sarah R
authors.initials: SR
authors.lastname: King
authors.forename: Kan
authors.initials: K
authors.lastname: He
authors.forename: Pancras C
authors.initials: PC
authors.lastname: Wong
authors.forename: Alan R
authors.initials: AR
authors.lastname: Rendina
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.forename: Baomin
authors.initials: B
authors.lastname: Xin
authors.forename: Robert M
authors.initials: RM
authors.lastname: Knabb
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.forename: Patrick Y S
authors.initials: PY
authors.lastname: Lam
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D065427:Factor Xa Inhibitors; D006801:Humans; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D065427:Factor Xa Inhibitors; D011728:Pyridones; D015842:Serine Proteinase Inhibitors