Enzyme inhibition studies

A detailed study of the mechanism of APTl inhibition by the palmostatins was performed [7]. Lineweaver-Burke analysis revealed that with varying inhibitor concentration is increased and remains constant, which indicates 

50 values and kinetic parameters for inactivation and reactivation of APT1 by 

Palmostatin A ee=80%, palmostatin Bee=80%, palmostatin C 99%, palmostatin Dee 99%, n = 3, standard deviations from three determinations are reported. 

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CYP2D6 and CYP3A4 enzyme inhibition studies in human liver microsomes. Rapid Commun. Mass Spectrom. 14 207. 

C. Nomeir, A. A. Validation of higher-throughput high-performance liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry assays to conduct cytochrome P450s CYP2D6 and CYP3A4 enzyme inhibition studies in human liver microsomes. Rapid Commun Mass Spectrom 2000, 14, 207-214. 

Higher throughput screening with human cytochrome P450 to study P450-medi-ated metabolism is now available [38-40]. Similarly, rapid microhtre plate assays to conduct for example, P450 enzyme inhibition studies have been developed, using individually expressed CYP enzymes (Supersomes) [41]. 

The significance of these in vitro enzyme inhibition studies is uncertain, in view of the evidence that has been presented concerning the sensitivity of cancer cells to feedback inhibition by these nucleotides. On the other hand, 6-chloropurine inhibits the de novo biosynthesis of nucleic acid guanine but not of nucleic acid adenine in sarcoma 180 ascites cells [319],... 

Afzelius, L., Zamora, I., Ridderstrom, M., Andersson, T. B., Karlen, A., and Masimirembwa, C. M. (2001) Competitive CYP2C9 inhibitors enzyme inhibition studies, protein homology modeling, and three-dimensional quantitative structure-activity relationship analysis. Mol. Pharmacol. 59, 909-919. 

In our early work, we attempted the alkylation of the amine 81 with various carbohydrate triflates, namely 82-84 [57]. Somewhat disappointingly, the main products isolated were the alkenes, e.g. 85 and 86. Only a small amount of the desired N-linked carbasugar, e. g. 87 was ever obtained. At one stage we attempted an alkylation of the amine 81 with the triflate 82 and with the triflate 84 in the presence of potassium carbonate to our surprise, carbamates were formed, 88 and 89 These two carbamates have subsequently been deprotected to give the methyl -o-glucoside 90 and the free sugar 91, interesting candidates for enzyme inhibition studies [57]. 

Conduct in vitro and in vivo enzyme-induction and enzyme-inhibition studies in animal models, if appropriate. 

A quick comparison of QSAR 1.82-1.84 reveals the strong similarity between the avian and mammalian models. In fact because of its increased stability, chicken liver DHFR has often been used as a surrogate for human DHFR in enzyme-inhibition studies. The intercepts, coefficients with Tr g and optimum tt q for avian (6.33, 1.01, 1.9), human (6.07, 1.07, 2.0), and mouse leukemia (6.12, 0.98, 1.76) can be compared to the corresponding values for P. carinii (6.48, 0.73, 3.99) and Leishmania major (5.05, 0.65, 4.54). ( SAR 1.81 and 1.87 are not included in the comparison because crude pigeon enzyme was used in... 

Following conversion to the triphosphate, the role of the azido substituent of AZT in the interaction of the drug with viral RT is also uncertain. Enzyme inhibition studies have demonstrated that HIV RT has a of 2.8 for the natural substrate thymidine-5 -triphosphate, whereas... 

Palamanda, J.R. Eavreau, L. Lin, C.C. Nomeir, A.A. Validation of a rapid microtiter plate assay to conduct cytochrome P450 2D6 enzyme inhibition studies. Drug Discov. Today 1998, 5, 466-470. 

The anticholinesterase activity of the oxadiazolones of this report was measured using housefly heads as the enzyme source and the method of EllraanO) was utilized to determine the enzyme activity. The conditions for the enzyme inhibition studies are shown below ... 

Displacement Studies. Enzyme-inhibition studies have similar requirements if the target molecule is an enzyme and the radiotracer used for quantification is an inhibitor. An alternate mechanism is based on substrate analogs, like F-FDG, which block enzymatic degradation, thus facilitating quantification. 

Competitive CYP2C9 inhibitors Enzyme inhibition studies, protein homology modeling, and three-dimensional quantitative structure-activity relationship analysis. Mol. Pharmacol. 59,909-919. 

The next enzyme in the biosynthetic pathway to norepinephrine and epinephrine, dopamine p-hydroxylase. has been the subject of extensive research into its chemical mechanism and the subject of many enzyme inhibition studies. The inhibitors known to date, however, are primarily of basic biochemical research interest and have no therapeutic relevance. The same is true of phenylethanolamine-N-methyltransferase. the last enzyme in the biosynthesis of epinephrine in the adrenal medulla. 

Toxicokinetic and enzyme inhibition studies have established that aldicarb can readily bioactivate in most organisms into aldicarb sulfoxide and sulfone, which are more potent inhibitors of acetylcholinesterase. These metabolites may further convert into oximes and nitriles, all of which may be excreted out mostly in the urine. Studies in cows have shown that about 90% of aldicarb eliminated out within 24 -honrs through urine, exhaled air and milk. Stndies in fish indicate that both the cytochrome P450 and flavin monooxygenase systems are involved in bioactivation of aldicarb to its snlfoxide (Perkins, Jr. and Schlenk 2000). 

C. M. Masimirembwa, Competitive CYP2C9 Inhibitors Enzyme Inhibition Studies, Protein Homology Modeling, and Three-Dimensional Quantitative Strucmre-Activity Relationship Analysis, Mol. Pharmacol, 2001, 59, 909-919. 

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