Structure- and property-based design of factor Xa inhibitors: pyrrolidin-2-ones with acyclic alanyl amides as P4 motifs.
Structure-based drug design was exploited in the synthesis of 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group with acyclic tertiary amide termini. Optimized hydrophobic contacts of one amide substituent in P4 were complemented by hydrophobicity-modulating features in the second, producing potent fXa inhibitors including examples with excellent anticoagulant properties.
Young
Robert J
RJ
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Rob.J.Young@gsk.com <Rob.J.Young@gsk.com>
Campbell
Matthew
M
Borthwick
Alan D
AD
Brown
David
D
Burns-Kurtis
Cynthia L
CL
Chan
Chuen
C
Convery
Máire A
MA
Crowe
Miriam C
MC
Dayal
Satish
S
Diallo
Hawa
H
Kelly
Henry A
HA
King
N Paul
NP
Kleanthous
Savvas
S
Mason
Andrew M
AM
Mordaunt
Jackie E
JE
Patel
Champa
C
Pateman
Anthony J
AJ
Senger
Stefan
S
Shah
Gita P
GP
Smith
Paul W
PW
Watson
Nigel S
NS
Weston
Helen E
HE
Zhou
Ping
P
D000409:Alanine / Q000737:chemistry*; D000577:Amides / Q000737:chemistry*; D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000990:Antithrombin III / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D015951:Factor Xa / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011758:Pyrroles / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000577:Amides; D000925:Anticoagulants; D011758:Pyrroles; D000990:Antithrombin III; D015951:Factor Xa; D000409:Alanine