Lead® compounds

This point emphasizes the importance of keeping an open mind, especially when testing for biological activity. Frequently, an analogue made in one field of medicinal chemistry is found to have an unexpected application in another field altogether. 

In order to design a drug with a particular biological activity, the medicinal chemist requires a lead compound—a compound which shows a useful pharmaceutical activity. 

The level of activity may not be very great and there may be undesirable side-effects, but the lead compound provides a start. By altering the structure using the strategies already mentioned, a useful drug may be developed with improved 

On occasions, the useful biological activity may only be a minor property or a side-effect of a compound. The aim then would be to enhance the side-effect and eliminate the major biological activity. The story of the antiulcer agent cimetidine (Fig. 7.29) is a case in point. The desired biological property was selective antagonism of histamine receptors in the stomach. The lead compound was a histamine agonist with a very weak antagonism for the receptors of interest. 

In such situations, the medicinal chemist wants to alter the molecule such that the major biological activity is eliminated and the side-effect is boosted until it becomes the dominant effect. Once this has been achieved, the drug can be fine-tuned as 

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PbEu (anti-knock agents), radiation and sound shields, in paints, high quality glass. World production 1980 4 0 megatonnes. Lead compounds are toxic and hazardous to health. 

The development of catalytic converters for combustion of unburned hydrocarbons prohibits a return to lead compounds and henceforth refiners are turning to oxygenated compounds that must be used as a gasoline component therefore, in amounts much greater than those of lead compounds. 

In addition to their antiknock properties, organic lead compounds possess bactericidal properties and motor fuels with lead are known to inhibit bacterial growth during storage in contact with water. With the disappearance of lead-based compounds, it is necessary to incorporate biocides from the cyclic imine family, (piperidine, pyrrolidine, hexamethyleneimine), alkylpropylene diamines or imidazolines (Figure 9.2). 

The protection of the environment implies the elimination of lead compounds, first of all because of their individual toxicities and second because these derivatives or their products of decomposition poison catalytic converter catalysts. 

Historically, drug absorption, distribution, metabolism, excretion, and toxicity ADMET) studies in animal models were performed after the identification of a lead compound. In order to avoid costs, nowadays pharmaceutical companies evaluate the ADMET profiles of potential leads at an earlier stage of the development... 

The metal is very effective as a sound absorber, is used as a radiation shield around X-ray equipment and nuclear reactors, and is used to absorb vibration. White lead, the basic carbonate, sublimed white lead, chrome yellow, and other lead compounds are used extensively in paints, although in recent years the use of lead in paints has been drastically curtailed to eliminate or reduce health hazards. 

In order to parameterize a QSAR equation, a quantihed activity for a set of compounds must be known. These are called lead compounds, at least in the pharmaceutical industry. Typically, test results are available for only a small number of compounds. Because of this, it can be difficult to choose a number of descriptors that will give useful results without htting to anomalies in the test set. Three to hve lead compounds per descriptor in the QSAR equation are normally considered an adequate number. If two descriptors are nearly col-linear with one another, then one should be omitted even though it may have a large correlation coefficient. 

The first step in designing a new compound is to find compounds that have even a slight amount of usefulness for the intended purpose. These are called lead compounds. Once such compounds are identified, the problem becomes one of refinement. Computational techniques are a fairly minor part of finding lead compounds. The use of computer-based techniques for lead compound identification is usually limited to searching databases for compounds similar to known lead compounds or known to treat diseases with similar causes or symptoms. 

Once a number of lead compounds have been found, computational and laboratory techniques are very successful in rehning the molecular structures to yield greater drug activity and fewer side elfects. This is done both in the laboratory and computationally by examining the molecular structures to determine which aspects are responsible for both the drug activity and the side effects. These are the QSAR techniques described in Chapter 30. Recently, 3D QSAR has become very popular for this type of application. These techniques have been very successful in the rehnement of lead compounds. 

Lead Azide. The azides belong to a class of very few useflil explosive compounds that do not contain oxygen. Lead azide is the primary explosive used in military detonators in the United States, and has been intensively studied (see also Lead compounds). However, lead azide is being phased out as an ignition compound in commercial detonators by substances such as diazodinitrophenol (DDNP) or PETN-based mixtures because of health concerns over the lead content in the fumes and the explosion risks and environmental impact of the manufacturing process. 

Lead fluorides are highly toxic and should be handled with great care. The ACGIH adopted toxicity value for lead compounds as Pb is TWA 0.15 mg/m and for fluorides as F 2.5 mg/m. PbF is prepared by the action of elemental fluorine on very dry Pbp2 at 280—300°C (15). 

These chemorational techniques have generated great interest in, and high expectations for, the acceleration of development of innovative pesticides. However, many purportedly successful appHcations of QSAR procedures have reHed on the quaHtative insights traditionally associated with art-based pesticide development programs. Retrospective QSAR analyses have, however, been helpful in identifying the best compounds for specific uses (17). Chemorational techniques have also found some appHcations in the development of pesticides from natural product lead compounds, the best known examples being the synthetic pyrethroid insecticides (19) modeled on the plant natural product, pyrethmm. 

In the near-infrared, Al Ga As and In Ga As P lasers, and in the far-infrared lead compound semiconductor lasers are tunable by varying temperature and operating current. Many exceUent spectroscopic studies have been performed using them. However, they do have relatively limited tuning ranges for any one device. 

Lead and its compounds are cumulative poisons and should be handled with recommended precautions. These materials should not be used in contact with food and other substances that may be ingested (see also Lead compounds). 

Lead is one of the most stable of fabricated materials because of excellent corrosion resistance to air, water, and soil. An initial reaction with these elements results in the formation of protective coatings of insoluble lead compounds. For example, in the presence of oxygen, water attacks lead, but if the water contains carbonates and siUcates, protective films or tarnishes form and the corrosion becomes exceedingly slow. 

The lead-bearing components ate released from the case and other nordead-containing parts, followed by the smelting of the battery plates, and refinement to pure lead or specification alloys. The trend toward battery grid alloys having Httle or no antimony, increases the abiHty of a recovery process to produce soft lead (refined). As requited in the production of primary lead, each step in the secondary operations must meet the environmental standards for lead concentration in ait (see Air pollution Lead compounds, industrial toxicology). 

The particle size and chemical composition of lead and lead compounds affect the readiness with which lead is absorbed from the lungs and digestive tract (see Lead compounds, industrial toxicology). Larger particles and compounds having low aqueous solubiHty are less hazardous than finely divided particles and compounds of higher solubiHty. 

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