Lead generation phase

The degree of importance of the lead generation phase has for some time been underestimated and it is only in the past decade that the main actors in the field have understood its value. In fact, there is a paradigm shift [4] in the way scientists see this phase going from the idea of finding a lead to creating one. 

The first and third order terms in odd powers of the applied electric field are present for all materials. In the second order term, a polarization is induced proportional to the square of the applied electric field, and the. nonlinear second order optical susceptibility must, therefore, vanish in crystals that possess a center of symmetry. In addition to the noncentrosymmetric structure, efficient second harmonic generation requires crystals to possess propagation directions where the crystal birefringence cancels the natural dispersion leading to phase matching. 

LC/MS/MS techniques with selective and sensitive detection methods make it possible to quantitatively analyze samples from Caco-2 cell and PAMPA buffer matrices. A high-throughput permeability screen with robust LC/MS technology can quickly generate information about structure-permeability relationships that are extremely valuable in the lead optimization phase for the selection of pre-clinical candidates with favorable oral bioavailability properties. 

After optimization, scientists test the lead compounds in more sophisticated models including pharmacokinetics, pharmacodynamics, and toxicity. The optimal molecule selected from these assessments is then declared a new dmg candidate and moves on to the next phase (development). If a program is successful, it may take a total of 3-6 years from target selection and validation through lead generation, lead optimization, and preclinical evaluation in animals to candidate selection for a potential new medicine. 

Combinatorial libraries are one significant source of compounds. Their preparation is described in great detail elsewhere in this volume. Millions of compounds can easily be generated by combinatorial techniques using relatively simple chemistry. This approach is very useful in the lead optimization phase, when subtle variations on a lead structure can be... 

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