Lead structures

Lead structure According to Valler and Green s definition a lead structure is a representative of a compound series with sufficient potential (as measured by potency, selectivity, pharmacokinetics, physicochemical properties, absence of toxicity and novelty) to progress to a full drug development program [12]. 

The lead discovery process is depicted in Figure 10.4-4 and shows how the different methods are interconnected. A lead structure can be discovered by serendipity. In rational drug design all information available about a target serves to direct... 

Distinguishing Molecules of Different Biol< ical Activities and Finding a New Lead Structure - An Example of Ligand-Based Drug Design... 

Even in this fiiirly diverse data set of structures, the dopamine and benzodiazepine agonists could be separated quite well only two neurons had collisions between these two types ol compounds. Even more importantly, however, we now know in which chemical space one would have to search For new lead structures for dopamine or for benzodiazepine agonists. 

Nowadays a broad range of methods is available in the field of chemoinfor-matics. These methods will have a growing impact on drug design. In particular, the discovery of new lead structures and their optimization will profit by virtual saeening [17, 66, 100-103]. The huge amounts of data produced by HTS and combinatorial chemistry enforce the use of database and data mining techniques. 

After a bioactive marine natural product lead structure has been identihed,... 

The hydantoin moiety has been utilized as a biostere for the peptide linkage, transforming a peptide lead into an orally available drug candidate. Therefore, an Arg-Gly-Asp-Ser tetrapeptide (18) lead structure was modified to a non-peptide RGD mimetic as an orally active fibrinogen receptor antagonist 19. ° ... 

The previous sections have described methods to obtain 2-pyridone scaffolds. Both in the construction of new materials and especially in drug design and development, there is a desire to be able to derivatize and optimize the lead structures. In the following sections, some recent developments using MAOS to effectively substitute and derivatize 2-pyridone heterocycles are described. The reaction types described range from electrophilic-, and nucleophilic reactions to transition metal-catalyzed transformations (Fig. 7). To get an overview of how these systems behave, their characteristics imder conventional heating is first described in brevity. 

QuickC, D.L.J. and Usherwood, P.N.R. (1990). Spider toxins as lead structures for novel pesticides In E. Hodgson and R.J. Kuhr (Eds.) Safer Insecticides Development and Use, 385 52. New York Marcel Dekker. 

G., and Hamy, F. Rational optimization of a HlV-1 Tat Inhibitor Rapid progress on combinatorial lead structures. Biotech-nol. Bioeng. 1999, 61, 155—164. 

Langer T, Hoffmann RD. Virtual screening an effective tool for lead structure discovery Curr Pharm Des 2001 7 509-27. 

Langer T, Wolber G. Virtual combinatorial chemistry and in silica screening efficient tools for lead structure discovery Pure Appl Chem 2004 76 991-6. 

Figure 8. (a) Field emission scanning electron micrograph of a lead structure before the nanocrystals are introduced. The light gray... 

The identification of non-peptidic lead structures remains a challenge. Screening of natural product extracts led to the identification of two po-lyhydroxylated biphenyls ((10a) and (10b), Figure 2.13) that show submicromolar inhibition of the viral protease [156]. A recent report discloses polyesters of glucose (11) and gallic acid (12) as micromolar inhibitors of the NS3 protease [157]. 

The biological profile of the optimized lead structure emerging from these studies, compound (15a), was extensively investigated both in vitro and in vivo. The in vitro pattern of activity was in general excellent inasmuch... 

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. 

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