Optimization phase

Assion A, Baumert T, Bergt M, Brixner T, Kiefer B, Seyfried V, Strehle M and Gerber G 1998 Control of chemical reactions by feedback-optimized phase-shaped femtosecond laser pulses Sc/e/ ce 282 919... 

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...

The development of maraviroc (21), much like other chemokine receptor antagonists, started with a high-throughput screen employing a competition binding assay and led to the hit compound UK-107,543. Chemical optimization of this compound led to the development candidate UK-427,857 during this optimization phase, a parallel characterization of the compounds was performed... 

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. 

Virtual combinatorial compound libraries can be constructed and docked against the target [40 2]. This latter approach is likely to be more suitable for the fragment-optimization phase of a project, when the virtual library can be constructed around an initial fragment hit, with varying substitution patterns on pre-defined attachment points. The compounds can then be docked either in an imrestrained fashion, or, more usefully, using the 3D structure of the initial hit as a constraint or restraint [35]. 

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. 

The method development and optimization phase is completed with test method description drafted according to the method development results. The following method evaluation tests will continue with direct involvement of the customer (receiving laboratory). The goal is to check whether the developed late phase method performs adequately in different labs. 

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.

---