Optimization campaign

Wajge, R. M. and G. V. Reklaitis. An Optimal Campaign Structure for Multicomponent Batch Distillation with Reversible Reaction. Ind Eng Chem Res 37 (5) 1910-1916 (1998). 

Lead optimization involves more than just optimizing for target potency. New technology allows early lead optimization campaigns to address and consider multiple parameters and inputs for each round of iterative library synthesis. These inputs allow for the rapid development of potent compounds with drug-like profiles, as opposed to just potent compounds. These data also provide quick kills to individual leads or series and allow the lead optimization effort to re-direct resources toward more productive leads (1-5, 8-20). 

Combining all above-mentioned technologies and paradigms for synthesis, screening and DMPK evaluation affords an aggressive, expedited process for chemical lead optimization (1, 12-21). This protocol allows one to two synthetic chemists to support a chemical lead optimization effort with accelerated timelines that deliver proof-of-concept compounds within 6 months and clinical candidates within 12 months of the initiation of a lead optimization campaign. 

Papageorgiou L.G. and Pantelides C.C. 1996. Optimal campaign planning/scheduling of mnltipur-pose batch/semicontinuons plants. 2. Mathematical decomposition approach, Ind. Eng. Chem. Res., 35, 510-529. 

The analysis was based on two lead optimization projects. Project A represents a lead optimization campaign against an enzyme target that spanned approximately 4 years, between 2004 and 2007, and involved the synthesis and testing of 2154 unique... 

Given that for slope of the size versus affinity relationships are very consistent (AMW = 64 18 per log unit of affinity increase p-Kd)> the maximal affinity for a given optimized fragment could be predicted [74], Alternatively, the binding efficiency index [38] (BE = (pJfd/MW)) should remain constant throughout a fragment and lead optimization campaign. 

Aryl fluorides are a much more common structural motif, ubiquitously explored in lead optimization campaigns where a phenyl ring is part of the pharmacophore. Whilst these moieties offer the potential to prepare an -labeled analogue of a highly optimized ligand, the introduction of fluorine to these rings late in a synthetic scheme can present a considerable challenge and both nucleophilic and electrophilic processes have been developed [141-145,197]. 

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