Bioactive entities

For lead finding, the use of chemical compound collections and combinatorial libraries is indispensable to every pharmaceutical company for a timely and efficient discovery of novel bioactive entities [5]. Until recently, most attention was paid only to internal historic compound collections, maintained over several years of medicinal research [6]. Flowev-er, those libraries typically contain a limited number of structural classes as the result of past research projects which focused on biological activity islands .Today there is a growing interest in techniques that expand structural and - even more important - biological diversity, this perhaps being accomplished by the direct acquisition of an external compound collection, or by the use of internal or external synthesis capacities [7]. 

A few typical examples wherein the hyberdisation was accomplished commencing from two bioactive entities i.e., implementation of the full-salol principle occurred, as stated under ... 

Polyphosphoesters (PPEs) are phosphorus-containing polymers with repeating phosphoester (P-O) linkages in the backbone (Scheme 6.1). The pentavalent nature of phosphorus allows the introduction of various side chains such as bioactive entities through P-O, P-N, and P-C bonds. 

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. 

Over a century ago, empirical observation was made that organic nitrates, including glyceryl trinitrate (GTN), alleviate angina. Since then, GTN has been a mainstay therapy for angina and cardiac failure, even with the possible loss of effectiveness (tolerance) over extended dosing [55] and the risk of platelet hyperactivity in GTN-tolerant patients [54]. Despite this venerable therapeutic history, the mechanism of GTN bioactivation to NO is speculative at best [38]. In 1967, some 15 years before identification of NO as a biological entity, GTN was the first nitrovasodilator shown... 

The NIH has set up a consortium called the Molecular Libraries Screening Center Network (MLSCN), which performs HTS on assays provided by the research community. It currently has more than 100,000 chemically diverse compounds. This is an initiative of the Molecular Libraries Roadmap, which also has another two components Cheminformatics and Technology Development. The aim is to generate a comprehensive database of chemical compounds and their bioactivities to enhance the capability for the development of new drug entities. 

The high attrition rate of new chemical entities (NCEs) in preclinical and clinical phases can be attributed to many factors. According to Kola and Landis [50], NCEs fail mainly to insufficient efficacy, bioavailability, safety, toxicological and economic reasons. All these factors are somehow interrelated - a less soluble drug might be less bioactive and thus less efficient. Additionally, the attrition rate can depend on the therapeutic area the drug comes from. For example, compounds tend to fail more for CNS and oncology indications than in other therapeutic areas [50]. 

Exploration of the molecular basis of human disease will continue to provide additional targets for drug discovery, while a better understanding of marine ecological interactions at the molecular level can be used to guide the selection of novel sources and novel screens. This multidisciplinary approach to discovery of marine-derived drugs will likely result in the continued discovery of unique bioactive chemical entities and new ways to address the treatment of human disease. 

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