Lead Optimization in Pharmaceutical Discovery and Development

Authored by: C.K. Atterwill , M.G. Wing

Encyclopedia of Pharmaceutical Science and Technology

Print publication date:  July  2013
Online publication date:  July  2013

Print ISBN: 9781841848198
eBook ISBN: 9781351124874
Adobe ISBN:


 Download Chapter



Sensible lead candidate selection for preclinical development and registration should reduce the high rate of drug attrition, the cost of which increases with the distance that the failed drug candidate has proceeded down the research and development pipeline. It is estimated that “adverse” toxicokinetic and safety factors encountered during animal and human exposures in drug development account for approximately 60% of the reasons for termination during development (Fig. 1). Of this 60%, a combination of undesirable animal and human toxic events account for 21% of the total factors involved. Rates of attrition are high, especially during the early regulatory toxicology and clinical phases of testing. (Fig. 2). Not surprisingly, because of the large number of hits identified from primary high-throughput screens, lead candidate optimization has, therefore, emerged as a critical decision-making milestone from both ethical and commercial perspectives. The “models” or strategies for incorporation of a preclinical lead optimization stage are shown in Fig. 3. Essentially, the “old” or, in many cases, current, strategy is to take several lead candidate compounds through early small-scale clinical pharmacological/toxicokinetic/safety studies in vivo before a final selection is made following 1 month toxicology exposures on the lead development drug candidate for clinical exposure. Any later problems with the compound may then facilitate the design of a lead optimization “screen” at an earlier stage for possible follow-up compounds. A more modern and desirable approach would be (and is used in many cases now) to insert a mandatory in vitro ADME-Tox “screen” at the stage before the preliminary in vivo ADME-Tox exposures, which would then produce a “clean” lead development candidate (LDC) for full regulatory testing (Fig. 4). In short, there is a need for early rapid and robust screening assays which that will allow a lead series of compounds to be ranked for desirable or undesirable characteristics.

Search for more...
Back to top

Use of cookies on this website

We are using cookies to provide statistics that help us give you the best experience of our site. You can find out more in our Privacy Policy. By continuing to use the site you are agreeing to our use of cookies.