Drug discovery lead optimization phase

Most drug metabolism-based screens are performed during the lead optimization phase of drug discovery. Lead optimization begins once a compound is identified from primary screens and the desired potency, selectivity, and mechanism of... 

Kenakin, T. Predicting therapeutic value in the lead optimization phase of drug discovery. Nat. Rev. Drug Disc. 2003, 2, 429-438. 

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... 

In the past five years, lead optimization in drug discovery has changed significantly and no longer needs to be fragmented into separate hit-to-lead and lead optimization phases (2-5). Major advances have been made in HTS technologies, which have enabled detection of novel modes of target modulation. 

In the lead identification and lead optimization phases of discovery, there is greater focus on thermodynamic solubility measurements. Thermodynamic solubility assays are designed to determine the solubility of the stable crystalline form of the compound, since this is the physical form that will be sought in the development phase for orally administered drugs. As such, thermodynamic solubilities provide discovery projects with a better risk assessment of likely formulation issues in development. Thermodynamic solubilities, unlike kinetic solubilities, are less dependent on the initial physical form of the compound and being less time critical also tend to be more reproducible. This is particularly important from a molecular design perspective where chemists are seeking to modify molecular structure to improve solubility. 

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