title: Exploration of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides as potent, orally active Factor Xa inhibitors with extended duration of action.
abstract: Aiming to improve upon previously disclosed Factor Xa inhibitors, a series of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides were explored with the intent of increasing the projected human half-life versus 5 (projected human t(1/2)=6 h). A stereospecific route to compounds containing a 4-aryl-4-hydroxypyrrolidine scaffold was developed, resulting in several compounds that demonstrated an increase in the half-life as well as an increase in the in vitro potency compared to 5. Reported herein is the discovery of 26, containing a (2R,4S)-4-hydroxy-4-(2,4-difluorophenyl)-pyrrolidine scaffold, which is a selective, orally bioavailable, efficacious Factor Xa inhibitor that appears suitable for a once-daily dosing (projected human t(1/2)=23 h).
authors.affiliation: Michigan Laboratories, Ann Arbor Campus, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Van Huis
authors.forename: Agustin
authors.initials: A
authors.lastname: Casimiro-Garcia
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Bigge
authors.forename: Wayne L
authors.initials: WL
authors.lastname: Cody
authors.forename: Danette A
authors.initials: DA
authors.lastname: Dudley
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Filipski
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Heemstra
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Kohrt
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Leadley
authors.forename: Lakshmi S
authors.initials: LS
authors.lastname: Narasimhan
authors.forename: Thomas
authors.initials: T
authors.lastname: McClanahan
authors.forename: Igor
authors.initials: I
authors.lastname: Mochalkin
authors.forename: Michael
authors.initials: M
authors.lastname: Pamment
authors.forename: J Thomas
authors.initials: JT
authors.lastname: Peterson
authors.forename: Vaishali
authors.initials: V
authors.lastname: Sahasrabudhe
authors.forename: Robert P
authors.initials: RP
authors.lastname: Schaum
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Edmunds
mesh_terms: D000284:Administration, Oral; D018360:Crystallography, X-Ray; D006207:Half-Life; D006801:Humans; D011759:Pyrrolidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D011759:Pyrrolidines