Structure and property based design of factor Xa inhibitors: biaryl pyrrolidin-2-ones incorporating basic heterocyclic motifs.
Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating basic biaryl P4 groups, producing highly potent inhibitors with significant anticoagulant activities and encouraging oral pharmacokinetic profiles.
Young
Robert J
RJ
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom. Rob.J.Young@gsk.com
Borthwick
Alan D
AD
Brown
David
D
Burns-Kurtis
Cynthia L
CL
Campbell
Matthew
M
Chan
Chuen
C
Charbaut
Marie
M
Convery
Máire A
MA
Diallo
Hawa
H
Hortense
Eric
E
Irving
Wendy R
WR
Kelly
Henry A
HA
King
N Paul
NP
Kleanthous
Savvas
S
Mason
Andrew M
AM
Pateman
Anthony J
AJ
Patikis
Angela N
AN
Pinto
Ivan L
IL
Pollard
Derek R
DR
Senger
Stefan
S
Shah
Gita P
GP
Toomey
John R
JR
Watson
Nigel S
NS
Weston
Helen E
HE
Zhou
Ping
P
D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D008958:Models, Molecular; D011760:Pyrrolidinones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000925:Anticoagulants; D019086:Bridged Bicyclo Compounds, Heterocyclic; D065427:Factor Xa Inhibitors; D011760:Pyrrolidinones; D015842:Serine Proteinase Inhibitors