Exploration of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides as potent, orally active Factor Xa inhibitors with extended duration of action.
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).
Van Huis
Chad A
CA
Michigan Laboratories, Ann Arbor Campus, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA.
Casimiro-Garcia
Agustin
A
Bigge
Christopher F
CF
Cody
Wayne L
WL
Dudley
Danette A
DA
Filipski
Kevin J
KJ
Heemstra
Ronald J
RJ
Kohrt
Jeffrey T
JT
Leadley
Robert J
RJ
Narasimhan
Lakshmi S
LS
McClanahan
Thomas
T
Mochalkin
Igor
I
Pamment
Michael
M
Peterson
J Thomas
JT
Sahasrabudhe
Vaishali
V
Schaum
Robert P
RP
Edmunds
Jeremy J
JJ
D000284:Administration, Oral; D018360:Crystallography, X-Ray; D006207:Half-Life; D006801:Humans; D011759:Pyrrolidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
D011759:Pyrrolidines