Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
Add more filters










Database
Language
Publication year range
1.
J Med Chem ; 45(12): 2484-93, 2002 Jun 06.
Article in English | MEDLINE | ID: mdl-12036356

ABSTRACT

A novel series of diaryloxypyridines have been designed as selective nanomolar factor Xa (fXa) inhibitors for use as anticoagulants. In this paper, we describe our efforts to identify an additional interaction and a replacement for the distal amidine group that binds in the S3/S4 pocket of fXa. Introduction of a hydroxyl group para to the proximal amidine group increases the potency vs fXa by 1-2 orders of magnitude, which is the result of a hydrogen bond to Ser195 of the catalytic triad. A methyl imidazoline and a dimethylamide are good alternatives for the second amidine. These substitutions have increased the selectivity vs the related serine proteases trypsin and thrombin. The synthesis, in vitro activity, and hypothetical modes of binding to fXa based on trypsin crystallographic data are outlined.


Subject(s)
Amidines/chemical synthesis , Factor Xa Inhibitors , Serine Proteinase Inhibitors/chemical synthesis , Amidines/chemistry , Amidines/pharmacokinetics , Animals , Chromatography, High Pressure Liquid , Crystallography, X-Ray , Factor Xa/chemistry , Humans , Models, Molecular , Rats , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacokinetics , Structure-Activity Relationship , Thrombin/chemistry , Trypsin/chemistry
2.
J Org Chem ; 62(9): 2694-2703, 1997 May 02.
Article in English | MEDLINE | ID: mdl-11671627

ABSTRACT

Vacuum line kinetics studies have been made of the reaction in nitromethane between benzene and/or toluene, methoxyacetyl chloride (MAC), and AlCl(3) to produce benzyl or xylyl chlorides, CO, and a CH(3)OH(-)AlCl(3) complex. For both arenes, the rate law appears to be R = (k(3)/[AlCl(3)](0)) [AlCl(3)](2)[MAC]. When chloromethyl methyl ether (CMME) is substituted for MAC, a similar rate law is obtained. Both chloromethylation reactions yielded similar, large k(T)()/k(B)() ratios (500-600) and similar product isomer distributions with low meta percentages ( approximately 0.4) which suggest CH(3)OCH(2)(+) or the CH(3)OCH(2)(+)Al(2)Cl(7)(-) ion pair as a common, remarkably selective, electrophile. The kinetics of MAC decomposition to CMME and CO in the presence of AlCl(3) yielded the rate law R = k(2)[AlCl(3)](0)[MAC]. Here AlCl(3) is a catalyst (no CH(3)OH is formed), and thus the rate law is equivalent to the chloromethylation rate law. All three reactions have comparable reactivities, which is consistent with rate-determining production of the electrophile. Kinetics studies of benzene or toluene with SnCl(4) and MAC or CMME in dichloromethane were also completed. With MAC and benzene the rate law is R = k(3)[SnCl(4)](0)[MAC][benzene] and with toluene R = k(2)[SnCl(4)](0)[MAC]. MAC decomposition, again followed by CO production, was unaffected by the presence of either aromatic and obeyed the rate law R = k(2)' [SnCl(4)](0)[MAC] where k(2) approximately k(2)'. Chloromethylation with CMME followed the rate law R = k(3)[SnCl(4)](0)[CMME][arene] for benzene and toluene and produced a k(T)()/k(B)() ratio and product isomer distributions very similar to those determined with AlCl(3) in nitromethane, further supporting a common electrophile. Low-temperature (13)C and (119)Sn FT-NMR and Raman spectroscopic studies suggest the existence of a weak 1:1 adduct between MAC and SnCl(4) of the type RCXO --> SnCl(4), with electron donation to the metal through carboxy oxygen. Finally, an explanation is provided for the range of chloromethylation k(T)()/k(B)() values and product isomer percentages published in the literature.

SELECTION OF CITATIONS
SEARCH DETAIL
...