Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with monoaryl P4 motifs.
Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa inhibitors, incorporating neutral and basic monoaryl P4 groups, ultimately producing potent inhibitors with effective levels of anticoagulant activity and extended oral pharmacokinetic profiles. However, time dependant inhibition of Cytochrome P450 3A4 was a particular issue with this series.
Kleanthous
Savvas
S
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
Borthwick
Alan D
AD
Brown
David
D
Burns-Kurtis
Cynthia L
CL
Campbell
Matthew
M
Chaudry
Laiq
L
Chan
Chuen
C
Clarte
Marie-Olive
MO
Convery
Máire A
MA
Harling
John D
JD
Hortense
Eric
E
Irving
Wendy R
WR
Irvine
Stephanie
S
Pateman
Anthony J
AJ
Patikis
Angela N
AN
Pinto
Ivan L
IL
Pollard
Derek R
DR
Roethka
Theresa J
TJ
Senger
Stefan
S
Shah
Gita P
GP
Stelman
Gary J
GJ
Toomey
John R
JR
Watson
Nigel S
NS
West
Robert I
RI
Whittaker
Caroline
C
Zhou
Ping
P
Young
Robert J
RJ
D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D005170:Factor X / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000925:Anticoagulants; D011760:Pyrrolidinones; D005170:Factor X