Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
Add more filters










Database
Language
Publication year range
1.
Eur J Drug Metab Pharmacokinet ; 26(1-2): 123-8, 2001.
Article in English | MEDLINE | ID: mdl-11554426

ABSTRACT

Pregabalin [PGB, (S)-3-isobutyl GABA, CI-1008] is a derivative of the inhibitory neurotransmitter g-aminobutyric acid (GABA). It has shown anticonvulsant, analgesia and anxiety activity in animal models. In this report, blood-brain barrier (BBB) influx and efflux of PGB were investigated with microdialysis at efficacious doses in rats. BBB influx (CLin) and efflux (CLout) permeability for pregabalin were 4.8 and 37.2 microL/min/g brain, respectively, following an intravenous infusion to rats. The results indicate that PGB is brain penetrable, supporting its anti-epilepsy and other CNS pharmacology. Significant anticonvulsant action of PGB was detected between 2 and 8 hr post oral dose, which is lag behind ECF drug concentrations lees. A PK/PD link model was used to describe the counter-clockwise hysteresis relationship between pregabalin brain ECF concentration and the anticonvulsant effect in rats. The resulting Ce (concentration in effect compartment) versus effect profile exhibits a sigmoidal curve and the calculated ECe50 and Keo values were 95.3 ng/mL and 0.0092 min-1, respectively. The small Keo value suggests that the effect is not directly proportional to the amount of pregabalin in the ECF compartment possibly due to inherent delay.


Subject(s)
Amines , Anticonvulsants/pharmacology , Anticonvulsants/pharmacokinetics , Brain/metabolism , Cyclohexanecarboxylic Acids , GABA Antagonists/pharmacology , GABA Antagonists/pharmacokinetics , gamma-Aminobutyric Acid/analogs & derivatives , gamma-Aminobutyric Acid/pharmacology , gamma-Aminobutyric Acid/pharmacokinetics , Acetates/administration & dosage , Acetates/pharmacokinetics , Animals , Anticonvulsants/administration & dosage , Blood-Brain Barrier , Electroshock , GABA Antagonists/administration & dosage , Gabapentin , Indicators and Reagents , Infusions, Intravenous , Microdialysis , Models, Biological , Pregabalin , Rats , Rats, Wistar , Seizures/metabolism , gamma-Aminobutyric Acid/administration & dosage
2.
J Med Chem ; 41(5): 682-90, 1998 Feb 26.
Article in English | MEDLINE | ID: mdl-9513596

ABSTRACT

We prepared a series of alpha-substituted malonester amides that were evaluated for their ability to inhibit acyl-CoA:cholesterol O-acyl transferase activity in vitro and to lower plasma total cholesterol levels in a variety of cholesterol-fed animal models. Compounds of this series were also useful in examining the relationship between adrenal toxicity and ACAT inhibition. One compound from this series, 9f, was a potent inhibitor of ACAT in both the microsomal and cellular assays. It was also bioavailable as determined by both a bioassay and a HPLC-UV assay. This compound was evaluated in both guinea pig and dog models of adrenal toxicity and compared to tetrazole amide 15. In the most sensitive species, the dog, both of these compounds achieved good plasma levels; however, compound 9f caused adrenal necrosis, whereas compound 15 had no effect on the adrenal gland. This adds to the growing body of evidence that the adrenal toxicity observed with ACAT inhibitors may not be mechanism related.


Subject(s)
Adrenal Glands/drug effects , Adrenal Glands/pathology , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/toxicity , Malonates/pharmacology , Malonates/toxicity , Phenylacetates/pharmacology , Phenylacetates/toxicity , Sterol O-Acyltransferase/antagonists & inhibitors , Amides/pharmacology , Amides/toxicity , Animals , Anticholesteremic Agents/chemical synthesis , Biological Availability , Cholesterol/blood , Cholesterol, Dietary/administration & dosage , Chromatography, High Pressure Liquid , Dogs , Enzyme Inhibitors/chemical synthesis , Female , Guinea Pigs , Male , Malonates/chemical synthesis , Mice , Microsomes, Liver/enzymology , Necrosis , Phenylacetates/chemical synthesis , Rats , Rats, Sprague-Dawley , Tetrazoles/pharmacology , Tetrazoles/toxicity
3.
J Med Chem ; 39(12): 2354-66, 1996 Jun 07.
Article in English | MEDLINE | ID: mdl-8691430

ABSTRACT

A series of tetrazole amide derivatives of (+/-)-2-dodecyl-alpha-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5- acetamide (1) was prepared and evaluated for their ability to inhibit acyl-CoA: cholesterol O-acyltransferase (ACAT) in vitro and to lower plasma total cholesterol in vivo. For this series of compounds, our objective was to systematically replace substituents appended to the amide and tetrazole moieties of 1 with structurally diverse functionalities and assess the effect that these changes have on biological activity. The ensuing structure-activity relationship (SAR) studies identified aryl (7b) and heteroaryl (7f,g) replacements for 2,4,6-trimethoxyphenyl that potently inhibit liver microsomal and macrophage ACAT in vitro and exhibit good cholesterol lowering activity (56-66% decreases in plasma total cholesterol at 30 mg/kg), relative to 1, when compared in the acute rat model of hypercholesterolemia. Replacement of the alpha-phenyl moiety with electron-withdrawing substituents (13e-h), however, significantly reduced liver microsomal ACAT inhibitory activity (IC50 > 1 microM). This is in contrast to electron-donating substituents (13ij,m-q), which produce IC50 values ranging from 5 to 75 nM in the hepatic microsomal assay. For selected tetrazole amides (1, 7b, 13n,o), reversing the order of substituents appended to the 2- and 5-positions in the tetrazole ring (36a-d), in general, improved macrophage ACAT inhibitory activity and provided excellent cholesterol-lowering activity (ranging from 65% to 77% decreases in plasma total cholesterol at 30 mg/kg) in the acute rat screen. The most potent isomeric pair in this set of unsubstituted methylene derivatives (13n and 36a) caused adrenocortical cell degeneration in guinea pigs treated with these inhibitors. In contrast, adrenal glands taken from guinea pigs treated with the corresponding alpha-phenyl-substituted analogs (7b and 36c) were essentially unchanged compared to untreated controls. Subsequent evaluation of 7b and 36c in a rabbit bioassay showed that both compounds and/or their metabolities were present in plasma after oral dosing. Unlike 7b and 36c, compound 1 and related 2,4,6-trimethoxyanilides (13j, 30c,d) showed poor oral activity in the rabbit bioassay. Nevertheless, in cholesterol-fed rabbits, both systemically available (7b, 36c) and poorly absorbed inhibitors (1, 36d) were more effective in lowering plasma total cholesterol than the fatty acid amide CI-976.


Subject(s)
Anticholesteremic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Sterol O-Acyltransferase/antagonists & inhibitors , Tetrazoles/pharmacology , Animals , Anticholesteremic Agents/chemical synthesis , Anticholesteremic Agents/chemistry , Arteriosclerosis/prevention & control , Cholesterol/blood , Cholesterol, Dietary/pharmacokinetics , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Guinea Pigs , Hypercholesterolemia/chemically induced , Hypercholesterolemia/drug therapy , Macrophages/enzymology , Male , Microsomes, Liver/enzymology , Molecular Structure , Rabbits , Rats , Structure-Activity Relationship , Tetrazoles/chemical synthesis , Tetrazoles/chemistry
SELECTION OF CITATIONS
SEARCH DETAIL
...