Chlorothiophenecarboxamides as P1 surrogates of inhibitors of blood coagulation factor Xa.
Neutral chlorothiophenecarboxamides bearing an amino acid and a substituted aniline were synthesized and investigated for their factor Xa inhibitory activity in vitro. From selected 2-methylphenyl morpholinones the solution properties were determined. The most soluble and active compounds were then investigated in different animal species to compare the pharmacokinetic parameters. This led to a potent, water soluble and orally bioavailable candidate for further development: EMD 495235.
Mederski
Werner W K R
WW
Merck KGaA, Preclinical Pharmaceutical Research, 64271 Darmstadt, Germany. mederski@merck.de
Cezanne
Bertram
B
van Amsterdam
Christoph
C
Bühring
Karl-Ulrich
KU
Dorsch
Dieter
D
Gleitz
Johannes
J
März
Joachim
J
Tsaklakidis
Christos
C
D000818:Animals; D004285:Dogs; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors; D013876:Thiophenes; D015951:Factor Xa