Lead compounds definition

The elements show increasing metallic character down the group (Table 14.6). Carbon has definite nonmetallic properties it forms covalent compounds with nonmetals and ionic compounds with metals. The oxides of carbon and silicon are acidic. Germanium is a typical metalloid in that it exhibits metallic or nonmetallic properties according to the other element present in the compound. Tin and, even more so, lead have definite metallic properties. However, even though tin is classified as a metal, it is not far from the metalloids in the periodic table, and it does have some amphoteric properties. For example, tin reacts with both hot concentrated hydrochloric acid and hot alkali ... 

There seems to be a linear relationship between the mean value of L and the first ionization potential (IP) of MMe4 when M is Si, Ge, Sn and probably Pb as well. As the IP of PbMe4 is regarded as uncertain31b and only one data set for lead derivatives was available, making the L value for lead uncertain, no definite conclusion regarding the fit of lead compounds in this relationship can be reached. The only L value available for carbon at this time is reliable but does not fit the L-IP relationship. 

This section describes some of the biological research experiments that could, and in most cases should, be conducted to evaluate the potential of a lead compound to become a developmental candidate. Figure 3 shows where these developability experiments fit into the drug discovery and development process. These nondefinitive developability studies may also uncover problems that have to be resolved before the definitive preclinical development studies required to support an IND submission are started and before the clinical protocols to evaluate the safety and efficacy of the drug candidate in humans are designed. 

This is the year that the lead compound s correct structure was reported in a journal. Please note that some of the compounds (e.g. 3, 23 and 31), were isolated many years before a definitive structure was determined, while the structure of some of the compounds were disclosed in earlier patents. 

This chapter has reviewed the basic principles of computer-aided drug design, and several strategies of how it can be successfully integrated with combinatorial chemistry to develop highly effective site-focused libraries. Diversity plays a key role, as the more diverse set of compounds tested that fit the site-focused criteria, the more information is retrieved to improve the site-focused definition, which further directs the search in diversity space. In addition, if good hits are found, the information can be fed back to find compounds close in diverse space to the hit. This new paradigm for structure-based combinatorial chemistry should provide a powerful tool for rapid discovery of novel, potent lead compounds in the years to come. 

Once the assay and assay format have been decided upon, the next step in the discovery process is to initiate compound screening for the purpose of identifying hits or lead compounds. The fundamental requirement is that the assay results identify a collection of actives or hits. The definition of hit varies between organizations, but most accept the definition that the compound shows a confirmed structure, shows a confirmed dose response, exhibits an IC50 < lOpM potency, and is a member of a chemotype that is amenable to analoging and fast follow-on synthesis. 

These two objectives are discussed together because many of the selection criteria for screening compounds are important to fulfill both objectives, namely physical chemical properties and chemical purity and stability. Especially with respect to optimizability, a violation of the selection criteria discussed here is not a definite reason for exclusion, but it is a liability of the compound, which needs to be addressed during the optimization of the compound that follows the discovery of the hit. The more such liabilities a compound exhibits, the more difficult the optimization of a lead compound will be. Also, not every violation of a technology compatibility criterion is a hard reason for exclusion, but rather it increases the potential of a compound to cause artifacts under a certain assay technology appropriate experimental procedures are required to detect these artifacts. 

If the network indeed places highly active compounds in close vicinity vdth each other, compounds from the SPECS library colocalizing with highly active propafenone derivatives should also be active. Finally, seven compounds with completely different chemical scaffolds were retrieved and pharmacologically tested [32]. Two out of them showed inhibitory activity with IC50 values in the submicromolar range, which definitely renders them new lead compounds for P-gp (Figure 7.9). 

Systematic development cycles are more likely to be efficient and should result in a definite specification for the lead compound Scheme 1 shows a t5rpical flow chart for the characterization that leads to the development of specifications for the lead compound. 

A small but important class of atmospheric aerosol particles are the ice nuclei. These nuclei promote the freezing of water drops in clouds (see Fletcher, 1962). In this way they play a definite role in the formation of precipitation in mixed clouds containing both water drops and ice crystals. This kind of precipitation formation is due to the fact that the saturation vapour pressure over ice is smaller than over liquid water. In this way ice crystals grow by condensation while drops tend to evaporate. Thus, if human activity emits ice nuclei to the atmosphere the precipitation distribution can be modified. Results of measurements show that in the vicinity of steel works and aluminum foundries the concentration of ice nuclei active at a temperature of — 20 °C is unusually high. It is believed that this is caused by the presence of some metal oxides in the air (Pruppacher, 1973). More recent studies on ice nuclei also showed that lead compounds (e.g. Pbl 2) in exhaust gases of vehicles also have ice nucleating ability. It is believed, however, that anthropogenic ice nuclei cannot play an important role, except in local scale processes (see Pruppacher, 1973). 

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