Phase lead optimization

Fig. I The desired attributes of a lead molecule. Often, molecules identified by any screening strategy might satisfy optimal criteria for only a subset of these attributes and most laboratories would proceed with a medicinal chemistry campaign banking on improving the rest in a subsequent lead optimization phase...

For the evaluation of a possible relationship between the molecular structure of a potential candidate and its transport abilities to cross the epithelial membrane of the gut, the mechanism or route of transport must be known [1,4]. This is due to the structural requirements for the transcellular route being different from the paracellular route. During the lead optimization phase - when many mechanistically based studies are performed - the cell culture-based models can also be used with great confidence. 

LC/MS/MS techniques with selective and sensitive detection methods make it possible to quantitatively analyze samples from Caco-2 cell and PAMPA buffer matrices. A high-throughput permeability screen with robust LC/MS technology can quickly generate information about structure-permeability relationships that are extremely valuable in the lead optimization phase for the selection of pre-clinical candidates with favorable oral bioavailability properties. 

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

Pharmacokinetics and toxicity have been identified as important causes of costly late-stage failures in drug development. Hence, physicochemical as well as ADMET properties need to be fine-tuned even in the lead optimization phase. Recently developed in silica approaches will further increase model predictivity in this area to improve compound design and to focus on the most promising compounds only. A recent overview on ADME in silica models is given in Ref [128]. 

Fig. 14.10 Example for multidimensional optimization on relevant properties during the lead optimization phase from leads to a development candidate. After some iteration, compound properties are either improved or show no further optimization potential.

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... 

The combined score from the fingerprint and physicochemical models was the best to confirm a logical trend from lead optimization to launched drugs. Indeed, as shown in Figure 13.4, the best scored compounds were checked for the phase in which they belonged and the average scores suggested that, as a trend, compounds predicted as promiscuous are found more often in the lead optimization phase than... 

Combinatorial libraries are one significant source of compounds. Their preparation is described in great detail elsewhere in this volume. Millions of compounds can easily be generated by combinatorial techniques using relatively simple chemistry. This approach is very useful in the lead optimization phase, when subtle variations on a lead structure can be... 

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