TRANSAMINATION RESULTS IN FORMATION OF METHYLENECYCLOPROPANEPYRUVIC ACID, WHICH UNDERGOES DECARBOXYLATION TO METHYLENECYCLOPROPANE ACETIC ACID; PYRIDOXAL PHOSPHATE PLUS MG(2+) IONS AND THIAMINE PYROPHOSPHATE, MG(2+) IONS PLUS COENZYME-A ARE THE COFACTORS INVOLVED IN THE TWO REACTION STEPS.
Numerous abnormal metabolites were identified in large amounts in the urine of hypoglycin-treated rats... . analysis. ... Ten of them have not been previously associated with hypoglycin administration: these are several hydroxy compounds, including those from the valine and isoleucine pathways, 2-oxo-adipic acid, n-butyrylglycine and isovaleryl glucuronide. These results indicate that the pathways of isoleucine and valine metabolism are inhibited at their respective acyl-CoA dehydrogenation steps, as is the case for fatty acid, leucine and lysine metabolism, as previously shown.
... 14C- and 3H-labelled palmitic acid was administered with hypoglycin to rats, and radioactivity was measured in urinary dicarboxylic acids... . Both isotopes were incorporated into adipic and sebacic acids, indicating a precursor-product relationship. Glutaric acid was, essentially, unlabelled. Preferential incorporation of C-16, relative to C-1 of palmitate ... could be deduced ... . It thus appears that omega-oxidation of the fatty acid intervenes predominantly at an intermediate stage of chain-shortening, when inhibition of beta-oxidation by hypoglycin becomes more pronounced.
来源:Hazardous Substances Data Bank (HSDB)
代谢
低血糖素A，现在简称为低血糖素，通过转氨作用和氧化脱羧作用代谢为亚甲基环丙基乙酸（MCPA）。
Hypoglycin A, which is now simply called hypoglycin, is metabolized by means of transamination and oxidative decarboxylation to methylene cyclopropyl acetic acid (MCPA).[
来源:Hazardous Substances Data Bank (HSDB)
毒理性
副作用
神经毒素 - 其他中枢神经系统神经毒素
Neurotoxin - Other CNS neurotoxin
来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases
... Injection of hypoglycin into fasted rats maintained on a standard diet caused severe prostration, hypothermia and a massive dicarboxylic aciduria. Rats maintained on a diet containing clofibrate appeared normal after injection of hypoglycin, but had a marked dicarboxylic aciduria which was less than that induced in rats on a normal diet. After administration of hypoglycin, butyryl-CoA and decanoyl-CoA, but not palmitoyl-CoA, dehydrogenase activities were strongly inhibited (80-95%) in the livers of animals on a standard diet. Clofibrate feeding decreased the inhibition of these dehydrogenases to about 40-60%. It was concluded that although clofibrate protects against the toxic effects of hypoglycin, some enzyme inhibitions as indicated by dicarboxylic aciduria are only partly prevented.
...Clofibrate feeding apparently protected the animals against the toxic, hypoglycemic and hypothermic effects of hypoglycin...and completely prevented the ultrastructural damage caused by hypoglycin. After hypoglycin administration, hepatic mitochondrial butyryl-CoA dehydrogenase activity was inhibited by more than 90% and, surprisingly, the activity of the peroxisomal enzymes studied was largely preserved. When hypoglycin was given to rats fed on a clofibrate-containing diet, the oxidation of decanoylcarnitine, which was incomplete after hypoglycin treatment alone, remained incomplete with uncoupled mitochondria, but became apparently complete with coupled mitochondria. In the latter condition, there was a slowing of the rate during the last quarter of the pulse of oxygen uptake. Further, butyryl-CoA dehydrogenase activity was much less affected by hypoglycin in clofibrate-fed animals. ...
ADMIN OF GLYCINE (75 MG/KG, IP) TO RATS INJECTED WITH HYPOGLYCIN (150 MG/KG, IP) PREVENTED DEATH, HYPOGLYCEMIA, AND HYPOTHERMIA AND GREATLY DECR THE RISE IN PLASMA CONCN OF ISOVALERATE PLUS 2-METHYLBUTYRATE, BUTYRATE, AND METHYLENECYCLOPROPYLACETATE, AN END PRODUCT OF HYPOGLYCIN METAB.
Treatment consists primarily of gastrointestinal decontamination and supportive care. ... In symptomatic patients or in adults with large intentional ingestions, activated charcoal should be administered. Respiratory support may be required in patients with depressed levels of consciousness and respiratory depression. General supportive care should be provided for treatment of hypoglycemia, hypotension and dysrhythmias. /CNS Depressant Plants/
The present invention relates to compounds of Formula (I):
1
wherein A
1
is methylene, ethylene or propylene group and A
2
is N or CR
5
, or stereoisomeric forms, stereoisomeric mixtures, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of HCV NS3 protease, and to pharmaceutical compositions and diagnostic kits comprising the same, and methods of using the same for treating viral infection or as an assay standard or reagent.
Peptide inhibitors of hepatitis C virus NS3 protein
申请人：——
公开号：US20020177725A1
公开（公告）日：2002-11-28
This invention relates to a novel class of peptides having the Formula (I):
1
Which are useful as serine protease inhibitors, and more particularly as Hepatitis C virus(HCV) NS3 protease inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of using the same in the treatment of HCV infection.
[EN] ALPHA-KETOAMIDE INHIBITORS OF HEPATITIS C VIRUS NS3 PROTEASE<br/>[FR] INHIBITEURS D'ALPHA-CETOAMIDES DE LA PROTEASE NS3 DU VIRUS DE L'HEPATITE C
申请人：DU PONT PHARM CO
公开号：WO2001040262A1
公开（公告）日：2001-06-07
The present invention relates to ketoamide and ketoester compounds of Formula (I): where W is -NH- or -O-, or stereoisomeric forms, stereoisomeric mixtures, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of HCV NS3 protease, and to pharmaceutical compositions and diagnostic kits comprising the same, and methods of using the same for treating viral infection or as an assay standard or reagent.
Alpha-ketoamide inhibitors of hepatitis C virus NS3 protease
申请人：——
公开号：US20020123468A1
公开（公告）日：2002-09-05
The present invention relates to ketoamide and ketoester compounds of Formula (I):
1
wherein W is —NH— or —O—, or stereoisomeric forms, stereoisomeric mixtures, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of HCV NS3 protease, and to pharmaceutical compositions and diagnostic kits comprising the same, and methods of using the same for treating viral infection or as an assay standard or reagent.
Purified &bgr;-amino acids are of considerable interest in the preparation of pharmacologically active compounds and industrial precursors. Although enantiomerically pure &bgr;-amino acids can be produced by standard chemical synthesis, this traditional approach is time consuming, requires expensive starting materials, and results in a racemic mixture which must be purified further. However, DNA molecules encoding lysine 2,3-aminomutase can be used to prepare &bgr;-amino acids by methods that avoid the pitfalls of chemical synthesis. The present invention provides a method of producing enantiomerically pure &bgr;-amino acids from &agr;-amino acids comprising catalyzing the conversion of an &agr;-amino acid to a corresponding &bgr;-amino acid by utilizing a lysine 2,3-aminomutase as the catalyst.
纯化的&bgr;-氨基酸在制备药理活性化合物和工业前体方面具有相当大的意义。虽然对映体纯的&bgr;-氨基酸可以通过标准化学合成法生产，但这种传统方法耗时长，需要昂贵的起始原料，而且会产生外消旋混合物，必须进一步纯化。然而，编码赖氨酸 2,3-氨基转化酶的 DNA 分子可以用来制备 &bgr;-氨基酸，其方法避免了化学合成的缺陷。本发明提供了一种从&agr;-氨基酸制备对映体纯&bgr;-氨基酸的方法，包括利用赖氨酸 2,3-氨基转化酶作为催化剂，催化&agr;-氨基酸转化为相应的&bgr;-氨基酸。
