Design and synthesis of glycolic and mandelic acid derivatives as factor Xa inhibitors.
A series of glycolic and mandelic acid derivatives was synthesized and investigated for their factor Xa inhibitory activity. These analogues are highly potent and selective inhibitors against fXa. In a rabbit deep vein thrombosis model, compound 26 showed significant antithrombotic effects (81% inhibition of thrombus formation) at 1.1 microM plasma concentration following intravenous administration.
Su
T
T
COR Therapeutics, Inc., 256 East Grand Avenue, South San Francisco, CA 94080, USA. tsu@corr.com
Wu
Y
Y
Doughan
B
B
Kane-Maguire
K
K
Marlowe
C K
CK
Kanter
J P
JP
Woolfrey
J
J
Huang
B
B
Wong
P
P
Sinha
U
U
Park
G
G
Malinowski
J
J
Hollenbach
S
S
Scarborough
R M
RM
Zhu
B Y
BY
D000083:Acetanilides; D000578:Amidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D001780:Blood Coagulation Tests; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D065427:Factor Xa Inhibitors; D005341:Fibrinolysin / Q000037:antagonists & inhibitors; D020128:Inhibitory Concentration 50; D007275:Injections, Intravenous; D008333:Mandelic Acids / Q000737:chemistry*; D010648:Phenylacetates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D020246:Venous Thrombosis / Q000188:drug therapy
D000083:Acetanilides; D000578:Amidines; D065427:Factor Xa Inhibitors; D008333:Mandelic Acids; D010648:Phenylacetates; D015842:Serine Proteinase Inhibitors; C442369:alpha-(3-amidinylphenoxy)-2-bromo-N-(5-(pyrrolidin-1-ylcarbonyl)phenyl)phenylacetamide; D005341:Fibrinolysin; C037938:mandelic acid