Lead development candidate

Genomics to Lead Development Candidate (Preclinical Lead Profile, PLP)... 

Fig. 3 Diagramatic representation of Old and New strategies for lead optimization of new pharmaceutical molecules. The top section indicates the Old (and in some cases, current) way in which pharmaceutical companies take Hits to lead development candidate through discovery and early preclinical development testing. Essentially, no high-throughput formal lead optimization exists in this model but is developed for backup compounds by using biomarkers identified during lead compound failure in vivo. The bottom section indicates the New way forward (used now by most major pharmaceutical companies). In this model, a formal in vitro PLOT battery is inserted early in development before preliminary in vivo ADME-Tox screening and subsequent lead development candidate selection.

Fig. 5 Platforms comprising the pre-clinical lead optimization technology (PLOT) filters in the selection of lead development candidate molecules in drug development.

Safety lead optimization efforts are used to maximize resources and early decision-making for the purposes of reducing costs and animal use and removing the least favorable compounds early during the discovery phase, when there is most flexibility in optimizing the candidate molecule. The ultimate goal is to identify a lead development candidate that has the most superior safety characteristics and, for those safety issues identified, a well-characterized risk assessment to reduce clinical attrition due to toxicity and inform the clinical development plan. 

Abstract High quality leads provide the foundation for the discovery of successful clinical development candidates, and therefore the identification of leads is an essential part of drug discovery. Many factors contribute to the quality of a lead, including biological, physicochemical, ADME, and PK parameters. The identification of high quality leads, which are needed for successful lead optimization, requires the optimization of all of these parameters. Parallel optimization of all parameters is the most efficient way to achieve the goal of lead identification. 

Two papers described the optimization of LLE and physicochemical properties in a series of pyrazole HTV nonnucleoside reverse transcriptase inhibitors (NNRTIs) and the selection of lersivirine (6) as a development candidate [15,16]. The early lead (7) was relatively lipophilic (clogP = 4.3), rapidly metabolized in human liver microsomes and had an LLE of only 1.9 [pIC50 (HIV RT) - clogP] [15]. An optimization program targeting increased LLE in less lipophilic compounds of low MW (to... 

These agents have been effective for initial episodes of UTIs however, resistance develops rapidly, and their use is limited. These agents also lead to candidal overgrowth. They are useful primarily for chlamydial infections. 

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.

Rogers BL. (2004) Bacterial targets to antimicrobial leads and development candidates. Curr Opin Drug Discov Dev 7 211-222. 

In summary, in silico approaches to aid in removing D DI should be actively applied in early lead development. The application of these models in early drug discovery will reduce the frequency and cost of drug candidates that require clinical DDI studies. In the future, it is possible that a great majority of CYP-based DDI issues will be removed during lead development. 

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... 

At lead selection, after which typically more chemistry effort is invested, the selected compounds can be profiled in a broader (secondary) panel of assays, hopefully confirming the selective nature of the leads. If this is the case, spot checking in the primary panel through the optimization phase may be sufficient to ensure selectivity is retained while the required potency at the primary target is achieved. If the selected leads are still rather promiscuous, or certain individual unwanted liabilities remain, these should be monitored by testing in the primary panel (or in additional individual assays) and improved upon during lead optimization. Tfie broader panel can then be applied again to the selected development candidates for a final check and these may even be extended further to additional specialized panels for added security. 

Although no biopharmaceutical product delivered to the bloodstream via the pulmonary route has been approved to date, several companies continue to pursue active research and development programmes in the area. Amongst the leading product candidates is Exubera , an inhalable dry powder insulin formulation currently being evaluated by Pfizer and Aventis Pharma in Phase III clinical studies. The inhaled insulin is actually more rapidly absorbed than if administered subcutaneously and appears to achieve equivalent glycaemic control. While promising, final approval or otherwise of this product also depends upon additional safety studies which are currently under way. 

Optimized leads identified in the secondary screening phase of a HT-R D program are then taken to the tertiary screening phase to generate commercial development candidates. This usually takes the form of a conventional mini- or pilot-plant. 

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