The discovery of (2R,4R)-N-(4-chlorophenyl)-N- (2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (PD 0348292), an orally efficacious factor Xa inhibitor.
Herein, we report the discovery of novel, proline-based factor Xa inhibitors containing a neutral P1 chlorophenyl pharmacophore. Through the additional incorporation of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one 22, as a P4 pharmacophore, we discovered compound 7 (PD 0348292). This compound is a selective, orally bioavailable, efficacious FXa inhibitor that is currently in phase II clinical trials for the treatment and prevention of thrombotic disorders.
Kohrt
Jeffrey T
JT
Michigan Laboratories, Ann Arbor Campus, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. jeffrey.kohrt@pfizer.com
Bigge
Christopher F
CF
Bryant
John W
JW
Casimiro-Garcia
Agustin
A
Chi
Liguo
L
Cody
Wayne L
WL
Dahring
Tawny
T
Dudley
Danette A
DA
Filipski
Kevin J
KJ
Haarer
Staci
S
Heemstra
Ron
R
Janiczek
Nancy
N
Narasimhan
Lakshmi
L
McClanahan
Thomas
T
Peterson
J Thomas
JT
Sahasrabudhe
Vaisheli
V
Schaum
Robert
R
Van Huis
Chad A
CA
Welch
Kathleen M
KM
Zhang
Erli
E
Leadley
Robert J
RJ
Edmunds
Jeremy J
JJ
D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000990:Antithrombin III / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004285:Dogs; D006801:Humans; D008297:Male; D011728:Pyridones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship
D000925:Anticoagulants; C523986:N-(4-chlorophenyl)-N-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-4-methoxypyrrolidiine-1,2-dicarboxamide; D011728:Pyridones; D011759:Pyrrolidines; D000990:Antithrombin III