Leads identifying

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. 

However, the majority of positive leads identified so far have been isolated from the natural reservoir of peptides. A possible explanation for this may be that these peptides have undergone natural selection over billions of years, resulting in enhanced in vivo stability. Another explanation may be that the majority of random peptide sequences from chemical and recombinant libraries do not fold into stable structures (12) however, this may not nessesarily render these peptides more susceptible to proteolytic degradation. 

Although it is essential to test promising compounds in mice and other animal models prior to human trials, it is economically, ethically and often scientifically preferable to use cell-based and in vitro approaches to eliminate inactive compounds before commencing animal trials. Clearly, animal models are not an appropriate screen for combinatorial libraries of platinum complexes they should be used to study further the promising leads identified by high-throughput methods. 

Houma T. Recent advances in de novo design strategy for practical lead identifieation. Med. Res. Rev. 2003 23 606-632. 

Fig. 11 The structurally novel lead identified by the pharmacophore search. Lead optimization was focused to regions indicated.

The data show that from 2002 to 1Q2009 the largest source of leads or SoC over this period consistently came from the kinase cross-screen (X-screen). The X-screen process is depicted schematically in Figure 1.5. Over half (53%) of all leads identified derived from this approach. For our purposes, a hit is an active compound that comes out of a screen, and a lead is a more advanced compound that has significant promise such that one has confidence that an optimization effort will lead to a clinical candidate. The other two target class... 

Table 4.7 Crystalline compounds of lead identified in street dusts [22].

Decision to investigate Social services/police decide whether case meets threshold for safeguarding Investigation lead identified End of next working day... 

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