Hit-to-lead phase

Partly due to the limited throughput of Caco-2 permeability measurements, the structure-activity evaluation of compounds tested in the hit-to-lead phase is done with minimal permeability information, at best. Given the importance of membrane permeability in drug absorption, early consideration of the permeability characteristics of hit compounds would enhance the drug-like quality, and ultimately the probability of success, of selected lead candidates. To incorporate permeability information into the hit-to-lead phase of the drug discovery process it is necessary that permeability measurements be made quickly and with small amounts of material. Thus, efforts have been made to automate and miniaturize the Caco-2 permeability assay. 

After the hit discovery process (often using high-throughput screening), early drug discovery is generally split into a hit to lead phase and a lead optimization phase, followed by the selection of development candidates (DCs) (Figure 12.2). In vitro... 

A smaller (prima ) panel of targets is usually sufficient during the hit to lead phase and lead optimization phases of a drug discovery program to detect promiscuous scaffolds and... 

Hit to lead phase Awareness Identify risks early... 

If a chemical hit (series) identified from screening has clear potential chemical liability that would limit the ability to develop the compound and related analogs then it is unlikely to be selected with high priority to move into the hit-to-lead phase. This is less of an issue for probe development, for example oral bioavailability is rarely a criteria for a chemical probe (even if desirable), similarly potential in vivo toxicity liabilities of a hit are not of concern for initiating a probe development program. While medicinal chemists and pharmacologists on a drug discovery or probe discovery team... 

During the early stages of drug discovery, prior to the availability of the first chemical matter (hit-to-lead phase). 

A Medicinal Chemistry Perspective on the Hit-to-Lead Phase in the Current Era of Drug Discovery... 

Affinity-Based Screening Methodoiogies and Their Appiication in the Hit-to-Lead Phase... 

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