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.
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom. Rob.J.Young@gsk.com
Robert J
RJ
Young
Alan D
AD
Borthwick
David
D
Brown
Cynthia L
CL
Burns-Kurtis
Matthew
M
Campbell
Chuen
C
Chan
Marie
M
Charbaut
Máire A
MA
Convery
Hawa
H
Diallo
Eric
E
Hortense
Wendy R
WR
Irving
Henry A
HA
Kelly
N Paul
NP
King
Savvas
S
Kleanthous
Andrew M
AM
Mason
Anthony J
AJ
Pateman
Angela N
AN
Patikis
Ivan L
IL
Pinto
Derek R
DR
Pollard
Stefan
S
Senger
Gita P
GP
Shah
John R
JR
Toomey
Nigel S
NS
Watson
Helen E
HE
Weston
Ping
P
Zhou
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