The Development of Medicinal Chemistry

Paracelsus (1493 to 1541) is credited with establishing the role of chemistry in medicine. It is evident in his oft-quoted, visionary view:

"it is the task of chemistry to produce medicines for the treatment of disease since the vital functions of life are basically chemical in nature [ ] all things are poisons, for there is nothing without poisonous qualities. It is only the dose which makes a thing a poison."

However, until the development of analytical and synthetic chemistry in the 19th century, the discovery of new therapeutic substances remained focused on the biological investigation of natural substances usually secured from the apothecary garden. The new chemical techniques enabled the isolation and manufacture of pure substances. First, reproducible extraction procedures yielded individual active compounds from natural products and, subsequently, toward the end of the century, de novo synthesis was achieved of the simpler natural products such as aspirin, which was first marketed by Bayer in 1899. The next logical step was to systematically modify existing biologically active compounds, referred to as lead compounds, in an attempt to improve on their drug-like properties. By the 1930s the pharmaceutical industry had begun a sustained period of productivity, identifying lead compounds and transforming them into effective new therapeutic agents. These lead compounds came from a variety of sources including natural products, endogenous chemical messengers (hormones, neurotransmitters, enzyme substrates, etc.), random screening of the output of industrial chemistry processes (e.g., dyestuffs), and in the case of so-called me-too programs, simply from an existing drug. The latter programs were based on improving the biopharmaceutical properties or safety profile of existing drugs acting at a particular target or the optimization of a known side-effect that was perceived as potential therapeutic benefit in its own right. The success of the burgeoning pharmaceutical industry from 1930 through 1980 and the impact of the medicines produced on the quality and longevity of life are beyond question (Figure 4.2).

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