Factor Xa inhibitors: S1 binding interactions of a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides.
Factor Xa inhibitory activities for a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides with different P1 groups are described. These data provide insight into binding interactions within the S1 primary specificity pocket; rationales are presented for the derived SAR on the basis of electronic interactions through crystal structures of fXa-ligand complexes and molecular modeling studies. A good correlation between in vitro anticoagulant activities with lipophilicity and the extent of human serum albumin binding is observed within this series of potent fXa inhibitors. Pharmacokinetic profiles in rat and dog, together with selectivity over other trypsin-like serine proteases, identified 1f as a candidate for further evaluation.
Chan
Chuen
C
CVU UK Medicinal Chemistry Department, GlaxoSmithKline Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom. chuen.8chan@gsk.com
Borthwick
Alan D
AD
Brown
David
D
Burns-Kurtis
Cynthia L
CL
Campbell
Matthew
M
Chaudry
Laiq
L
Chung
Chun-wa
CW
Convery
Máire A
MA
Hamblin
J Nicole
JN
Johnstone
Lisa
L
Kelly
Henry A
HA
Kleanthous
Savvas
S
Patikis
Angela
A
Patel
Champa
C
Pateman
Anthony J
AJ
Senger
Stefan
S
Shah
Gita P
GP
Toomey
John R
JR
Watson
Nigel S
NS
Weston
Helen E
HE
Whitworth
Caroline
C
Young
Robert J
RJ
Zhou
Ping
P
D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004285:Dogs; D015951:Factor Xa / Q000737:chemistry*; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011517:Prothrombin Time; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D008024:Ligands; D009025:Morpholines; D011759:Pyrrolidines; D012709:Serum Albumin; D013449:Sulfonamides; D015951:Factor Xa