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In an industry focused on reducing attrition, lead generation represents a critical stage in drug discovery wherein a considered choice of lead series can significantly reduce the time and resources committed to unpromising chemical series. To aid identification and selection of series with a specific mechanism of action, within property space suitable for the intended mode of administration, many modalities are brought into play and are discussed in this chapter. Aspects covered include the approaches used to find chemical start points, as well as some of the blind alleys that the investigator should avoid, and the need to consider lead-like properties in context of a line-of-sight to the final drug candidate. By way of help, examples are given of both successful and unsuccessful lead generation.

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