New active entities

The development of a single enantiomer as a new active substance should be described in the same manner as for any other new chemical entity. Studies should be carried out with the single enantiomer, but if development began with the race-mate then these studies may also be taken into account. Chiral conversion should be considered early on so that enantiospecific bioanalytical methods may be developed. These methods should be described in chemistry and pharmacy part of the dossier. If the opposite enantiomer is formed in vivo, then it should be evaluated in the same way as other metabolites. For endogenous human chiral compounds, enantiospecific analysis may not be necessary. The enantiomeric purity of the active ingredient used in preclinical and clinical studies should be stated. 

Research on the identification of vanilloid antagonists has been pursued more intensively in industry than in academia. Thus, a SciFinder search for new chemical entities endowed with this type of activity pulled out 34 entries from the proprietary literature, and only 14 from journal articles during the period January 2004 June 2006. The patent literature can be difficult to evaluate and compare with the published data. Bioactivity is often not disclosed (or commented), and activity can be broadly claimed for a series of lead structures without specifying their optimal substitution. On the other hand, analysis of the patent literature does not only complement the published data, but also offers a preview of information that will be eventually disclosed and detailed in journals. Given the relevance of proprietary literature in the realm of vanilloids research, the main trends emerging from its analysis will be briefly summarized. 

Laboratories are known to apply for the authorization of new active ingredients in order to ensure that the prices of new products are higher than those of products already on the market. Once marketed, products are subject to such strict price regulation that the authorities barely allow adjustment even for general inflation. We have calculated that only 30.05 per cent of the new chemical entities authorized for the first time in Spain between 1990 and 1997 were actually classified as therapeutic improvements at the time of their introduction onto the market. For this evaluation we used the definitions and data on therapeutic improvement released each year by the Ministry of Health and Consumer Affairs in their publication Informacion Terapeutica del Sistema Nacional de Salud. 

Lastly, pharmacogenomics could provide new tools for the design of more specific and active CNS pharmaceuticals. The efficacy of a broad spectrum of neuro-pharmaceutical drugs is often complicated by their inability to reach their site of action because of the BBB. One way to overcome this is to use carrier-mediated transport at the luminal and/or abluminal membranes of the endothelial cells of the BBB. This will provide a physiologically based drug delivery strategy for the brain by designing new chemical entities or fused proteins that can cross the BBB via these transporters. 

AUC and Cmax are commonly measured to identify safety ratios for new chemical entities. Since the analytical methods used for biotechnologically derived pharmaceuticals may lack specificity, a clinical marker of biological activity or efficacy may sometimes be more appropriate than exposure data. 

Clinical research groups are responsible for the discovery of new chemical entities, to target and interrupt disease pathways. It is common for drug products to come from families where the active backbone that targets the desired receptor is the same, and different side chains are added to achieve activity in the body. The development of thermodynamic methods that facilitate this approach will have an obvious advantage in reducing data requirements for the life science industries. 

Since the origin, the most efficient source of drugs and biological active molecules is Nature. As reported by Newman and Cragg in a recent review [1], at least 25-30% of New Chemical Entities (NCE) going under study for pharmaceutical and clinical applications are primarily derived from Nature (N) or Natural Derived (ND), while only 30% are merely synthetic, as reported in Figure 2. 

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