Inhibitor Evaluations

Linezolid Myelosuppression monitor CBC once weekly if more than 2 weeks of therapy Peripheral and/or optic neuropathy has been reported with long-term therapy Mild MAO inhibitor evaluate for potential drug-drug or drug-food interactions... 

Thus the aim of this text is to provide medicinal chemists and pharmacologists with a detailed description of enzyme-inhibitor evaluation as it relates directly to drug discovery efforts. These activities are largely the purview of industrial pharmaceutical laboratories, and I expect that the majority of readers will come from this sector. However, there is an ever-increasing focus on inhibitor discovery in academic and government laboratories today, not only for the goal of identifying... 

Cushman, D. W., Cheung, H. S., Sabo, E. F., and Ondetti, M. A. (1981). Angiotensinconverting enzyme inhibitors Evaluation of a new class of antihypertensive drugs. In "Angiotensin-Converting Enzyme Inhibitors Mechanism of Action and Clinical Implications", (Z. P. Horovitz, Ed.), pp. 1-25. Urban and Schwarzenberg, Baltimore and Munich. 

Newton, D. J., R. W. Wang, and A. Y. H. Lu. Cytochrome P450 inhibitors Evaluation of specificities in the in vitro metabolism of therapeutic agents by human liver microsomes. Drug Metab. Disp. 23 154-158, 1995. 

HIV-1 protease inhibitors were initially tested to determine dosing and interval administration (Markowitz et al., 1995 Danner et al, 1995). These studies provided key insights into the pharmacologic properties for this class of compounds. A direct result of these studies was the early recognition of resistance (since nonfully suppressive doses and intervals were initially tested) to HIV-1 protease inhibitors. The rapid clinical assessment of these medications began with an evaluation of the addition of HIV-1 protease inhibitors for patients with advanced immune destruction as defined by less than 100 CD4 cells. This was followed by HIV-1 protease inhibitor evaluation for patients with modest immune suppression, defined as less than 200 CD4 cells, and then for patients with minimal immune destruction (200-500 CD4 cells), and even exploratory studies for patients with no immune destruction (more than 500 CD4 cells). 

B. Example 2 CYP3A Classification of Inhibitors Evaluation of Substrate Independence... 

HPLC provides a simple method of evaluating protease activity using a standard peptide substrate and equipment available in most laboratories. The method is suitable for inhibitor evaluation and may be used for screening small to moderate numbers of compounds. 

Casanola-Martm, G.M., Marrero-Ponce, Y, Khan, M. T.H., Ather, A., Sultan, S., Torrens, F. and Rotondo, R. (2007b) TOMOCOMD-CARDD descriptors-based virtual screening of tyrosinase inhibitors evaluation of different classification model combinations using bond-based linear indices. Bioorg. Med. Chem., 15, 1483—1503. 

Finley PR, O Brien ]G, Coleman RW. Lithium and angiotensin-converting enzyme inhibitors evaluation of a potential interaction, j Clin Psychopharmacol 1996 ... 

Internally quenched fluorogenic substrate probes have been shown to be useful in a variety of contexts, from conventional enzymology and inhibitor evaluation, to searches for important new therapeutic protease targets. The development of automated methods for synthesis of these substrate probes has enabled access to a wide range of substrate sequences, and facilitated detailed studies of enzyme-substrate sub-site interactions. The selection of the Edans-Dabcyl fLuorophore-quencher pair has led to the synthesis of efficiently quenched peptide substrates containing more than 30 amino add residues. The overall versat bty of these substrate probes ensures widespread future application to studies of many new and existing proteases of interest. 

Finley PR, O Brien JG, Coleman RW. Lithium arid ai otensin-converting en me inhibitors evaluation of a X)tential mXeraeivxi.J ClinPsychophtumacol( 996) 16,68-71. 

The industry has always attempted to standardize materials and their applications. Despite great and protracted efforts to standardize test procedures, and there are many standard corrosion tests there are no standard tests for corrosion inhibitor evaluation. The reasons for this are complex as may become clear below. However, basically it had been thought that inhibitors, once evaluated under a specific set... 

To illustrate the above, inhibitor evaluations by means of the so-called "Wheel Test [iO] fail all three quality criteria. This test has in the past been used extensively to evaluate corrosion inhibitors for use in oilfield applications. The results are always based on weight loss and are, therefore, not unique. They are not relevtmt, because as the test bottles turn on the wheel to which they are affixed, the flow regime or agitation is not defined. The results are also not predictive, because the controlling variables do in general not reflect field conditions. Disregtirding these most basic quality criteria has in the past been, tind still is, a major resison for costly failures in the field of oil tmd gtis production. 

In other words, the quest for a standardized corrosion inhibitor evaluation test is as elusive as it ever was and continues to be so. 

Corrosion testing and corrosion inhibitor evaluation are done (apart from mechanistic studies) for the purpose of determining... 

FIG. 5—Contour plot of Iso-corrosion rate lines for J-55 at 100 ppm Inhibitor evaluated In the HSACT. The points indicate the experimental matrix and results. 

It is absolutely imperative that all corrosion inhibitor evaluations be made on metal specimens encountered in the field. It had been pointed out above that [27,25] the effective inhibitor concentration on two different oilfield steels (J-55 and L-80) was vastly different under severe conditions. Examples of this abound in the industry. Weldments of carbon steel piping containing a small amount of copper were more difficult to inhibit under relatively mild conditions. 

The effectiveness of inhibitors is affected by a number of environmental, physical, and metallurgical parameters. These variables interact with each other in unpredictable nonlinear fashion, and moreover, such interactions are inhibitor specific. This state of affairs negates the validity of screening or standardized testing. Relevant and predictable inhibitor evaluation must be carried out under conditions simulating as closely as possible those of ultimate usage. 

Hausler, R. H. and Stegmann, D. W., "Studies Relating to the Predictiveness of Corrosion Inhibitor Evaluations in Laboratory and Field Environments, SPE Production Engineering, August 1990, p. 286. 

Dawson, J. L., Miller, R. G., John, D. G., and King, R. A., "Inhibitor Evaluation Methodology for Oilfield Application, CORROSION/88, NACE Annual Conference, Paper No. 361,1988. 

Acidizing treatments are used to stimulate production by the acidic dissolution of undesirable materials on the walls of the producing formation or by pumping acid into the formation to improve permeability. Hydrochloric acid (HCl) is used for limestone formations. Hydrofluoric acid (HF) is added to the HCl for silicate formations. Inhibitors are added to the acid to protect steel tubing during the short period of exposure to acid during injection, and the following period when partially spent acid is returned to the surface. Suppliers use a variety of nonstandardized tests for acid inhibitor evaluation. 

Transport of gasoline and other refined products in steel pipelines may result in corrosion products that can create a product contamination problem. Internal corrosion of the pipeline can also have an adverse effect on pipeline capacity. Corrosion results from condensation of a water film on the pipe wall plus dissolved air or SRB in the product. Corrosion control is commonly achieved by adding a corrosion inhibitor. Evaluation of inhibitor performance can be done using NACE Test Method for Antirust Properties of Cargoes in Petroleum Product Pipeline (TM0172). This test method is a modification of ASTM D 665, Test Method for Rust-Preventing Characteristics of Inhibited Mineral Oil in the Presence of Water. 

Rust problems during usage of certain refined products, such as steam turbine oils, are controlled by addition of corrosion inhibitors. Evaluation of the performance of these inhibitors is done using ASTM D 665 or ASTM D 3603, Test Method for Rust-Preventing Characteristics of Steam Turbine Oil in the Presence of Water (Horizontal Disk Method). 

Inhibition of cholesteryl ester transfer protein (CETP), which mediates the transfer of cholesteryl esters from HDL particles and other lipoprotein fractions to atherogenic apo B-containing lipoproteins, leads to a substantial increase in HDL-Cconcentrations and also reduces LDL-C concentrations. Torcetrapib, the first CETP inhibitor evaluated in phase III clinical trials, caused increases in all-cause mortality and cardiovascular events, despite a dramatic increase in HDL-C concentrations. This paradox was explained by stimulation of aldosterone production, leading to increased blood pressure and low serum potassium [23]. Consequently, the large clinical outcomes trial, ILLUMINATE, was prematurely terminated in 2006. 

Inhibitor selection begins with the choice of physical properties. Must the inhibitor be a solid or liquid Are melting and freezing points of importance Is degradation with time and temperature critical Must it be compatible with other system additives Are specific solubility characteristics required This list can be extensive but is important because it defines the domain of possible inhibitors. It must be the first step of the inhibitor evaluation for any new system. The physical measurements are those routinely done as part of minimal quality acceptance testing. 

The challenge in inhibitor evaluation is to design experiments that simulate the conditions of the real-world system. The variables that must be considered include temperature, pressure, and velocity as well as metal properties and corrosive environment chemistry. System corrosion failures are usually localized and attributed to micro conditions at the failure site. Adequate testing must include the most severe conditions that can occur in the system and not be limited to macro or... 

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