Selective and dual action orally active inhibitors of thrombin and factor Xa.
The synthetic entry to new classes of dual fXa/thrombin and selective thrombin inhibitors with significant oral bioavailability is described. This was achieved through minor modifications to the sulfonamide group in our potent and selective fXa inhibitor (E)-2-(5-chlorothien-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-(morpholin-4-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide and these observed activity changes have been rationalised using structural studies.
Young
Robert J
RJ
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Rob.J.Young@gsk.com
Brown
David
D
Burns-Kurtis
Cynthia L
CL
Chan
Chuen
C
Convery
Máire A
MA
Hubbard
Julia A
JA
Kelly
Henry A
HA
Pateman
Anthony J
AJ
Patikis
Angela
A
Senger
Stefan
S
Shah
Gita P
GP
Toomey
John R
JR
Watson
Nigel S
NS
Zhou
Ping
P
D000818:Animals; D004285:Dogs; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors*
C521365:2-(5-chlorothien-2-yl)-N-((3S)-1-((1S)-1-methyl-2-(morpholin-4-yl)-2-oxoethyl)-2-oxopyrrolidin-3-yl)ethenesulfonamide; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D009025:Morpholines; D013449:Sulfonamides; D013917:Thrombin