Lead discovery history

In this chapter, we will describe the history and process of lead discovery from initial target identification and disease validation through the lead identification process itself, culminating in lead optimization and pre-clin-ical candidate selection. The full range of technologies and approaches that have been brought to bear on this complex activity will also be highlighted. 

The emergence of this "accidental" approach to drug discovery has its origins in early history with traditional natural herbal remedies that were passed from generation to generation in local communities or tribes. In fact, the early history of lead discovery is all about natural products and herbal remedies, the use of which dates back thousands of years. 

Alan P. Loeb. Birth of the Kettering Doctrine Fordism, Sloanism and the Discovery of Tetraethyl Lead. Business and Economic History 24 (1) (Fall 1995) 72-87. Source of the effect of TEL on public policy and government. 

The discovery of the binary (Yb,Ca)-Cd i-QCs [19] was a remarkable milestone in the history of QCs. The reasons are apparent they offered unique opportunities for structural analyses as they exhibited negligible chemical disorder, probably because of the large differences in the chemical crystallography of the components, in contrast to more common problems with ternary intermetallics. In addition, they also represented new (Tsai) types of AC cores and of i-QCs with a structural motif different from those of the Mackay and Bergman types (above) that were better known at the time. Without doubt, such a breakthrough discovery must lead to an era of related chemical explorations or tunings. Actually, almost all of the i-QC systems developed since 2000 are Tsai types [28,29], including our own additions (below). 

The discovery of the rare earth elements provide a long history of almost two hundred years of trial and error in the claims of element discovery starting before the time of Dalton s theory of the atom and determination of atomic weight values, Mendeleev s periodic table, the advent of optical spectroscopy, Bohr s theory of the electronic structure of atoms and Moseley s x-ray detection method for atomic number determination. The fact that the similarity in the chemical properties of the rare earth elements make them especially difficult to chemically isolate led to a situation where many mixtures of elements were being mistaken for elemental species. As a result, atomic weight values were not nearly as useful because the lack of separation meant that additional elements would still be present within an oxide and lead to inaccurate atomic weight values. Very pure rare earth samples did not become a reality until the mid twentieth century. 

Out on the river, the past could enter the stillness and exfoliate before the mind s eye, unfurling a dark fabric of interlocking casuistry. Forces, visible and hidden, stretching back into one s past migrations religious conversions—our self discoveries make us each a microcosm of the larger pattern of history. The inertia of introspection leads toward recollection, for only through memory is the past recaptured and understood. In... 

The concept of leadlikeness is central to drug discovery [44, 45]. As discussed earlier, the pharmaceuhcal industry, despite its century-old history, has done a poor job in documenhng the decision process, for example, why certain chemical steps were followed to reach a parhcular compound. This turns out to be a parhcularly important queshon today, since the industry is under pressure to reduce costs, increase productivity and provide high-quality leads in early preclinical discovery. Chemical aspects of the... 

Priestley continued experimenting, and soon he had written a manuscript titled The History and Present State of Electricity, with Original Experiments. In June of 1766 he was elected to the Royal Society, and his book on electricity was published in 1767. At this time, his experiments were primarily in physics. He had not yet developed the great interest in chemistry that was eventually to lead him to some very significant discoveries. 

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