Lead drug

The major impetus for the development of solid phase synthesis centers around applications in combinatorial chemistry. The notion that new drug leads and catalysts can be discovered in a high tiuoughput fashion has been demonstrated many times over as is evidenced from the number of publications that have arisen (see references at the end of this chapter). A number of )proaches to combinatorial chemistry exist. These include the split-mix method, serial techniques and parallel methods to generate libraries of compounds. The advances in combinatorial chemistry are also accompani by sophisticated methods in deconvolution and identification of compounds from libraries. In a number of cases, innovative hardware and software has been developed tor these purposes. 

Proudfoot, J. R. (2002). Drugs, leads, and drug-likeness An analysis of some recently launched drugs. Bioorgan. Med. Chem. Lett. 12 1647-1650. 

Cytochrome P450 enzymes have been the subject of a number of recent reviews in which their mechanism and scope of action are covered in much detail [1, 6, 10, 11]. The reader is referred to these articles for a more thorough account of the mechanism and reactivity of cytochrome P450 enzymes, while we present a few representative examples of cytochrome P450-catalyzed epoxidation below. The enzymes we chose are all involved in the biosynthesis of polyketide natural products. Polyketides are a large, structurally diverse family of compounds and have provided a wealth of therapeutically useful drugs and drug leads. 

Incorporating the Kirtas system with the International Plant Names Index and SNOW-MED allows movement of the historic text into an electronic format, identihcation of current plant names, and identihcation of the symptoms treated with the plants. To complete the mining of historic herbal texts for novel drug leads we use the Natural Products Alert (NAPRALERT ) database to compare the information extracted from the historic herbal text to the reports of plant use in the current literature. The NAPRALERT database provides a summary of plants ethnopharmacological use, biochemical activities, and isolated compounds [27]. By querying each plant (with the current plant name) it is possible to identify any reports in the current literature regarding the plant. As an example, Table 4.1 shows the NAPRALERT output for Cycas rumphii. 

It is possible to extract novel drug leads from historic herbal texts. However, manual extraction techniques are laborious. The automated extraction system we have developed makes it possible to identify potential novel drug leads in a high-throughput fashion. 

Winkler DA. Neural networks as robust tools in drug lead discovery and development. Mol Biotechnol 2004 27 139-68. 

Alvarez JC. High-throughput docking as a source of novel drug leads. Curr Opin Chem Biol 2004 8 365-70. 

Another example belonging to the class of domino processes initiated by an elimination was described by Gurjar and coworkers in their synthesis of the 2,4-dis-ubshtuted tetrahydrofuran 2-554 [288] this compound is a potent anti-asthmatic drug lead (Scheme 2.125) [289]. 

One advantage of whole-cell biotransformation that has not been addressed adequately in this chapter is the ability to modify compounds with complex structure, such as natural products. Natural products are ideal substrates for biotransformation reactions since they are synthesized in a series of enzymatic reactions by the whole cells. The modification of natural products by biotransformation has been reviewed recently by Azerad [ 13] and a majority of the modifications were carried out by whole-cell biotransformations. Additional examples of modification of natural products by whole-cell biotransformations can also be found in the review article by Patel [2]. Natural products are an important source of new drugs and new drug leads [53]. The use of biotransformation, especially whole-cell biotransformation, in modification of natural products for lead optimization and generating libraries of derivatives for S AR and screening studies is important for the pharmaceutical industry. 

Fig. 22.1 Mechanisms underlying substance abuse. Addictive behavior is seen as a cyclical process where anticipation of the pleasure resulting from use of the drug leads to failure of the psychological mechanisms that usually control consumption. Excess quantities of drug are taken and an unpleasant withdrawal state arises when drug levels fall. This leads to...

The scope for further developments in the chemistry of seven-membered heterocyclic systems is considerable, particularly with respect to multi-heteroatom component systems. New synthetic methods are needed for these systems and ring-fused derivatives. The demand for such systems is likely to be largely driven by the search for structurally novel drug leads. 

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