PubMed · 15812197
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Harry Büller, Giancarlo Agnelli. 2005. Introduction.. https://doi.org/10.1159/000083077
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Phenprocoumon belongs to the group of vitamin K antagonists (VKAs), for example warfarin and acenocoumarol. It is widely used for therapeutic anticoagulation and clinically administered as a racemate. Both enantiomers are partially metabolized by the polymorphic CYP2C9 enzyme. The pharmacokinetics are, however, substantially less dependent on CYP2C9 activity or genotype than for other CYP2C9-metabolised VKAs, and pharmacokinetic differences for the enantiomers are only minor. We have investigated the stereospecific pharmacokinetics of the monohydroxylated phenprocoumon metabolites in human plasma by achiral-chiral LC-LC-MS-MS coupling. In addition to the known metabolites, 4'-, 6-, and 7-hydroxyphenprocoumon, two other monohydroxylated metabolites (M1 and M2) were detected in plasma and human liver microsomal incubations. One of these was identified as 2'-hydroxyphenprocoumon by comparison with synthetic standards; the other seemed to be a side-chain-hydroxylated derivative. Analysis of enantiomeric metabolite ratios after a single oral dose of phenprocoumon revealed changes over time with an overall preponderance of the respective (R) enantiomers. The minor role of CYP2C9 in 4'-hydroxy-PPC formation and the effect of CYP2C9 genotype for (S)-6- and (S)-7-hydroxy-PPC were confirmed. M1 and M2 are formed highly stereoselectively, without dependence on CYP2C9 genotype. These may be interpreted as alternative metabolic pathways that render phenprocoumon less dependent on CYP2C9 activity or genotype.
Accumulating evidence has suggested that one of the mechanisms by which heparin inhibits metastasis is by blocking the P-selectin-based interaction of platelets with tumor cells. Here we demonstrate that the sulfate groups at C6/N and especially C6, but not C2 and C3, of heparin play a critical role in P-selectin recognition and that 2-O,3-O-desulfated heparin can block P-selectin-mediated A375 human melanoma cell adhesion. Our findings show that chemical modification of heparin, especially 2-O,3-O-desulfation, may result in a therapeutic agent that is anti-metastatic because it blocks unwanted P-selectin-dependent adhesion but that lacks dose-limiting anticoagulant effects.
Several non-amidino S1 derivatives of the 1,2-diaminobenzene-based scaffold (4) were synthesized and evaluated for their ability to bind to the active site and inhibit the human protease factor Xa. A subset of these compounds were also evaluated for their anticoagulant effects in human plasma as measured by prothrombin time (PT).