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With the intent to improve upon the projected human half-life of the previously disclosed Factor Xa inhibitor
5, a series of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides were explored. This work led to the discovery of
26, a selective, orally bioavailable, and efficacious Factor Xa inhibitor.
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 (2
R,4
S)-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).