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.
Michigan Laboratories, Ann Arbor Campus, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. jeffrey.kohrt@pfizer.com
Jeffrey T
JT
Kohrt
Christopher F
CF
Bigge
John W
JW
Bryant
Agustin
A
Casimiro-Garcia
Liguo
L
Chi
Wayne L
WL
Cody
Tawny
T
Dahring
Danette A
DA
Dudley
Kevin J
KJ
Filipski
Staci
S
Haarer
Ron
R
Heemstra
Nancy
N
Janiczek
Lakshmi
L
Narasimhan
Thomas
T
McClanahan
J Thomas
JT
Peterson
Vaisheli
V
Sahasrabudhe
Robert
R
Schaum
Chad A
CA
Van Huis
Kathleen M
KM
Welch
Erli
E
Zhang
Robert J
RJ
Leadley
Jeremy J
JJ
Edmunds
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