Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with biaryl P4 motifs.
Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating biaryl P4 groups, producing highly potent inhibitors with encouraging oral pharmacokinetic profiles and significant but sub-optimal anticoagulant activities.
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. 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
Chun-wa
CW
Chung
Máire A
MA
Convery
Henry A
HA
Kelly
N
N
Paul 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
D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D015195:Drug Design; D065427:Factor Xa Inhibitors; 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*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D011760:Pyrrolidinones; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides