Medicinal chemist, task

Although combinatorial chemistry and HTS have offered medicinal chemists a much broader range of possibilities for lead discovery and optimization, the number of chemical compounds that can be reasonably synthesized, which is sometimes called virtual chemistry space , is stiU far beyond today s capability of chemical synthesis and biological assay. Therefore, medicinal chemists continue to face the same problem as before which compounds should be chosen for the next round of synthesis and testing For chemoinformaticians, the task is to develop and utilize various computer programs to evaluate a very large number of chemical compounds and recommend the most promising ones for bench medicinal chemists. This process can be called virtual... 

Because fragment hits are smaller in size compared with a more drug-like HTS hit, there is much more room for the medicinal chemists to shape them into more novel leads and eventually lead series. This task is made easier if the fragment hits contain chemistry vectors for elaboration, which can be built in when assembling a fragment screening collection. 

The term combinatorial chemistry typically evokes images of huge libraries of molecules with members of 100,000 and even more. This type of large library is ideal for lead discovery, a situation in which a medicinal chemist is trying to cast a diverse structural net to search for activity. The lead optimization process is more specialized. The basic skeleton of the eventual candidate may already be known. Only the ideal substituents on the pharmacophore remain in question. While lead discovery and lead optimization are very different tasks, combinatorial chemistry can effectively play a role in both processes. 

Comparative molecular field analysis (CoMFA) is a modern, powerful extension of the classical QSAR methods that were developed in the 1960s.14 While Hansch analysis is simple to understand and fairly easy for any medicinal chemist to perform, CoMFA requires specialized software and an understanding of statistics. Since CoMFA is outside the experience of most synthetic chemists, pharmaceutical companies have dedicated computational chemistry groups to handle advanced QSAR tasks. 

The medicinal chemist is usually left alone with the task of prioritizing compounds that are often characterized with far more than 10 different computational and experimental parameters representing pharmacodynamic, pharmacokinetic, and physicochemical properties. 

Chapters 7, 8, and 9 describe the general tactics employed in developing an effective drug and also the difficulties faced by the medicinal chemist in this task. 

The fundamental difference between FBDD and HTS/HTL also means that the medicinal chemist plays a different role in each approach. In the HTS/HTL approach, the medicinal chemist is tasked to determine, often with limited chemistry resources, whether any HTS hit represents chemical matter that can be progressed in a timely fashion into LO. Much data must be analyzed and synthetically challenging analogs are generally avoided. The HTL chemist is part informatician, medicinal and synthetic chemist. 

A second major area in which the ready availability of the leukotrienes will undoubtedly prove of great value is in the discovery and development of new drug entities for the treatment of a variety of disease states. The leukotrienes have long been implicated in allergy and inflammation, and it seems safe to say that they will be found to play important roles in a variety of other disorders. Thus the development of drugs that stimulate, inhibit, or modulate their activities will hopefully prove useful in the treatment or cure of some of these disorders, and the ready accessibility of the pure leukotrienes by synthesis will facilitate the task of the pharmacologist and the medicinal chemist to discover agents that modify their action. 

The medicinal chemist confronted with the task of designing new drug entities in this area must be cognizant of the problems inherent in this disease process and the therapeutic qualifications expected of the new agent he has on his drawing board. While depression may at times be a pure disease, more often it is the overt expression of an underlying pathologic process which requires other than the mere symptomatic treatment of surface phenomena. 

Since in most cases it is impossible to test every molecule that is returned as a hit from a 3D database search, a selection of candidates for biological evaluation has to be done. Some tools are available in order to help the researcher to decide on which molecule(s) the attention should be focused on first. In addition to the medicinal chemist s knowledge and intuition, tools are available for this task. Some of them are listed below ... 

The purpose of this book is to highlight the importance of an area of research in the pharmaceutical industry known as process research and development and the challenges ahead. In the pharmaceutical industry, the medicinal chemist is faced with the daunting task of finding the next drug buster. This is by far the toughest job, because many medicinal chemists could work all their lives synthesizing molecules that may never make it to the market. 

Figure 19.23 Drug development-related multitasking. Although big pharma typically has specialized teams of pharmaceutical chemists dedicated to various of these activities, it is not uncommon in small pharma for drug discovery medicinal chemists to become actively involved with several (or all) of these tasks relative to each final lead compound that may progress into development. Note that the final toxicity and clinical batches must be prepared and formulated according to Good Manufacturing Practices (GMP) accompanied by Good Laboratory Practices (GLP) anaiyticai support.

---