Three Milestones

In general, there are three milestones for the drug discovery process. The first is the identification of a verified hit series (primary activity in a related series of molecules), the second the determination of a lead series (series with primary activity and drug-like properties), and the third a clinical candidate (activity, positive pharmaceutical, and pharmacokinetic properties devoid of toxicity). An example... 

With a view to transparent project execution, it is necessary to expound the most important safety aspects from time to time in a safety study according to the state of progress of the project and to discuss them in an expert group (project team, R D, safety department, engineering), to adopt them, and to document the results. Such a safety study is performed internally for all plants and should not be confused with that required under the extended requirements of the Stbrfallverordnung. In the course of plant planning, three milestones can be recorded [Henne 1994) ... 

This chapter will begin with the three-way-conversion (TWC) catalyst, which simultaneously converts CO, hydrocarbons and nitrogen oxides. TWC catalysts are currently used on all gasoline-powered passenger cars made in the US, as well as in many other world markets. The three milestones cited will be ceria, ceria-zirconia and close-coupled palladium. The first two of these bear on the central theme of gas-composition control, without which three-way conversion cannot be realized. The third milestone allowed the catalyst to become active at a much earlier point in the test cycle, leading to a major reduction in the amount of hydrocarbon emissions. 

I identified three milestones in the development of the concept of homology (1) Owen s distinction and clarification of homology and analogy (and homologue and analogue), (2) Patterson s distinction between taxic and transformational homology, and (3) Nelson s introduction of the concept of relationship into studies of homology. 

The main strategies of LEG emission mitigation is based on three milestones ... 

Even the most complicated aspects of thermodynamics are based ultimately on three rather simple and straightforward laws. These laws and their extensions sometimes run counter to our intuition. However, once truly understood, the basic principles of thermodynamics become powerful devices for sorting out complicated chemical and biochemical problems. At this milestone in our scientific development, thermodynamic thinking becomes an enjoyable and satisfying activity. 

There are three important milestones in the history of tliermodynamics and computation ... 

For the treatment of AIDS, TDF is now available in three commercial preparations, as such (Viread ), in combmation with emtricitabine (Truvada ) and m combination with emtricitabme and efavirenz (Atripla ). The latter represents a three-drugs-in-once combination piU, which has become available for the treatment of AIDS since July 2006. The different milestones mat marked the development and ultimate commercialization of Atripla (m 2006) smce the original identification of adefovir as an antiretroviral agent (m 1986) have been previously reviewed (De Clercq 2006, 2007a-c). 

Three common molecular shapes are associated with octahedral electron group geomehy. Most often, an inner atom with a steric number of 6 has octahedral molecular shape with no lone pairs. Example uses a compound of xenon, whose chemical behavior is described in the Chemical Milestones Box, to show a second common molecular shape, square planar. 

In 1687, Newton summarized his discoveries in terrestrial and celestial mechanics in his Philosophiae naturalis principia mathematica (Mathematical Principles of Natural Philosophy), one of the greatest milestones in the history of science. In this work he showed how his (45) principle of universal gravitation provided an explanation both of falling bodies on the earth and of the motions of planets, comets, and other bodies in the heavens. The first part of the Principia, devoted to dynamics, includes Newton s three laws of motion the second part to fluid motion and other topics and the third part to the system of the (50) world, in which, among other things, he provides an explanation of Kepler s laws of planetary motion. 

Unfortunately, in many milestone plans, especially in research, we see huge overconfidence in the original estimate of time requirements. This initial overconfidence can be attributed to two factors time pressure and personal frame of reference. If the talk around the water cooler claims that no project with a total timeline of more than two years will be funded, no milestone plans longer than that will be submitted, even if more time is realistically necessary. If the typical time a bench scientist needs for promotion to a management role is five years on average, milestone plans will not extend beyond two to three years. Accordingly, if all research steps have to fit this short time span, project planners will decide to set shorter individual milestones than are actually required. Little wonder that projects are abandoned prematurely or project overruns compared to originally expected timelines are so common. 

Figure 3.1 Hypothetical drug development pipeline, illustrating activities during a 12-month period. Three stages of drug development are indicated at the bottom of the figure. The corresponding milestones for each stage are indicated at the top of the figure. (Courtesy of Milestone Development Services, Newtown, Pa., USA.)...

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