Design and synthesis of orally active pyrrolidin-2-one-based factor Xa inhibitors.
A series of novel, non-basic 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group, was designed and synthesised. Within this series, the N-2-(morpholin-4-yl)-2-oxoethyl derivative 24 was shown to be a potent, selective fXa inhibitor with good anticoagulant activity. Moreover, 24 possessed highly encouraging rat and dog pharmacokinetic profiles with excellent oral bioavailabilities in both species.
Watson
Nigel S
NS
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Nigel.S.Watson@gsk.com
Brown
David
D
Campbell
Matthew
M
Chan
Chuen
C
Chaudry
Laiq
L
Convery
Máire A
MA
Fenwick
Rebecca
R
Hamblin
J Nicole
JN
Haslam
Claudine
C
Kelly
Henry A
HA
King
N Paul
NP
Kurtis
Cynthia L
CL
Leach
Andrew R
AR
Manchee
Gary R
GR
Mason
Andrew M
AM
Mitchell
Charlotte
C
Patel
Champa
C
Patel
Vipulkumar K
VK
Senger
Stefan
S
Shah
Gita P
GP
Weston
Helen E
HE
Whitworth
Caroline
C
Young
Robert J
RJ
D000284:Administration, Oral; D000818:Animals; D000990:Antithrombin III / Q000138:chemical synthesis / Q000494:pharmacology*; D001682:Biological Availability; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013917:Thrombin / Q000187:drug effects*
D005343:Fibrinolytic Agents; D011760:Pyrrolidinones; D000990:Antithrombin III; D013917:Thrombin