Backup compounds

Extensive pharmacology Mutagenicity Structural optimization Backup compounds Optimal agent selection... 

Lead optimisation is the synthetic modification of a biologically active compound, to fulfill all stereoelectronic, physicochemical, pharmacokinetic and toxicologic required for clinical usefulness (IUPAC). This phase begins with the first chemical lead or lead series selected for optimisation (i.e. the "lead series selected" milestone) and concludes with a decision for an optimized compound to enter preclinical development (i.e. the "pre-clinical candidate selected" milestone). This phase consists of testing of a compound to determine the chemical structure that has the optimum potency and selectivity for the target in question. The phase includes the search for backup compounds and may also include early ADME and toxicity evaluation. 

Objective The objective of this analysis was to develop a population PK/PD model based on the data after intravenous administration that allows to explore in silico which absorption characteristics would be required for other administration routes and/or which receptor binding properties are crucial for backup compounds. 

Adverse reactions are common at any stage of development and marketing, and this can cause cessation of a project. Prudent research teams have a so-called backup compound. Since the adverse reactions are common, companies insist on a backup even before considering taking a compound into clinical development. Many companies have spent years to discover a new target and went on to select Just one clinical candidate that failed, say, for some nonmechanism-related toxicity. Other companies had found better compounds for their target. Even a small company should have a backup molecule. Regrettably, many Biotechs fail to do this perhaps because they have so much conviction about the success of their principal molecule or so little time and money to develop a backup. 

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.

In 1993, as ABT-418 progressed through the course of early clinical trials, the pressing mission of the medicinal chemistry group was to prepare potential backup compounds. A matter of some debate was whether another isoxazole-like compound should suffice as a backup, or whether an entirely different series needed to be identified. A number of known nAChR ligands with diverse structures, such as anatoxin-a (5), l,l-dimethyl-4-phenylpiperazinium (6), and iV-methylcarbamyl choline (7), could potentially serve as lead compounds, and indeed many of these, as well as numerous isoxazole variants, were explored to at least some degree. 

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