Pharmaceuticals enzyme inhibitors

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... 

In an effort to interfere with CML progression, pharmaceutical scientists at Novartis first cloned and produced recombinant B CR-AB L kinase. With the availability of this enzyme in sufficient quantity and purity, a mass in vitro screen of a series of enzyme inhibitors was implemented to identify drug candidates that produce an optimum pharmaceutical profile. From these, they identified STI571 (Gleevec) as a lead candidate to block the kinase activity of BCR-ABL. STI571 acts as a competitive inhibitor of ATP binding to the enzyme, which leads to the inhibition of tyrosine phosphorylation of proteins involved in BCR-ABL signal transduction [39,40]. 

Other useful targets for pharmaceutical agents are thymidylate synthase and dihydrofolate reductase, enzymes that provide the only cellular pathway for thymine synthesis (Fig. 22-49). One inhibitor that acts on thymidylate synthase, fluorouracil, is an important chemotherapeutic agent. Fluorouracil itself is not the enzyme inhibitor. In the cell, salvage pathways convert it to the deoxynucleoside monophosphate FdUMP, which binds to and inactivates the enzyme. Inhibition by FdUMP (Fig. 22-50) is a classic example of mechanism-based enzyme inactivation. Another prominent chemotherapeutic agent, methotrexate, is an inhibitor of dihydrofolate reductase. This folate analog acts as a competitive inhibitor the enzyme binds methotrexate with about 100 times higher affinity than dihydrofolate. Aminopterin is a related compound that acts similarly. 

There is considerable interest in the design of highly specific irreversible enzyme inhibitors because of their potential use as therapeutic agents. Part of the research program of most pharmaceutical companies is the rational design of drugs based on mechanistic ideas from enzymology, biochemistry, and chem-... 

A fibrin clot containing adsorbed plasmin inhibitors is difficult to define in a chemical or physical sense. Generally, when enzyme reactions occur at surfaces, the porosities and adsorption properties erf which are variable, the reproducibility of enzyme assay methods is questionable. The proteinoses, to which belong the most important pharmaceutical enzymes, may present some difficulties when natural substrates (protein ) are prescribed. Here, the application of a parallel run with a reference standard is recommended. 

A derivative UV spectrophotometric method was used by Bonazzi et al. for the determination of benazepril hydrochloride and other angiotensin converting enzyme inhibitors in their pharmaceutical dosage forms [17],... 

The same authors also applied capillary electrophoresis to the study of benazepril hydrochloride and several angiotensin-converting enzyme inhibitors [43]. Separation of the compounds was performed by means of two phosphate buffers (each 0.1 M) at pH 7 and 6.25, respectively [42], Due to the highest selectivity of the first mentioned running buffer, the same system has been applied for the quantification of benazepril and other compounds in their corresponding pharmaceutical formulations. It was found that the possibility of simultaneous identification and quantification of the active ingredient in the finished products was especially attractive, and that excipients do not adversely affect the results. This article deals with the validation of some parameters of the quantitative analysis, namely linearity, precision, accuracy, and robustness [43],... 

The reservoir patch has a similar bioadhesive component but pharmaceutical formulations containing certain excipients, such as penetration enhancers and enzyme inhibitors, can be placed in the center of the design. A rate-controlling polymer membrane can be designed to control the drag release. 

With the exception of S-metolachlor, all the molecules listed under the column Final Target are used in pharmaceutical formulations. Dilitiazem is a Ca2+ antagonist, while Cilazapril is an angiotensin-converting enzyme inhibitor. Levofloxacin is an antibacterial, and cilastatin is used as an in vivo stabilizer of the antibiotic imipenem. S-metolachlor is a herbicide sold under the trade name of DUAL MAGNUM. Although the structures of the final targets are more complex than those of the intermediates, enantioselective syntheses of the intermediates are the most crucial steps in the complex synthetic schemes of these molecules. 

More detailed studies of epimerization in the azepanone series indicated that these compounds were configurationally stable over a pharmaceutically relevant time-scale [19]. Structure-activity relationships developed in previous series were applied successfully to the azepanone scaffold, yielding extremely potent enzyme inhibitors that exhibited good diastereomeric selectivity as well as reasonable selectivity versus cathepsin K homologues. 

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